You searched for subject:(genomic instability).
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University of Oxford
1.
Lopez-Martinez, David.
Characterisation of novel phosphorylation sites on FANCD2 and their role in the Fanconi anaemia pathway.
Degree: PhD, 2018, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:1a749320-e434-41e3-8b5d-32c5481c0dee 
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770584
► Interstrand crosslinks (ICLs) are a highly deleterious form of DNA damage because they link the two strands of DNA, blocking replication, transcription and chromosome segregation.…
(more)
▼ Interstrand crosslinks (ICLs) are a highly deleterious form of DNA damage because they link the two strands of DNA, blocking replication, transcription and chromosome segregation. At the center of ICL repair is the FANCD2/FANCI complex, recruitment of which onto the ICL is a critical step for repair. Monoubiquitination of both FANCD2 and FANCI lead to their retention on chromatin and is essential for subsequent repair. However, recent evidence shows that FANCD2 monoubiquitination takes place only after recruitment to DNA (Liang et al., 2016). If the monoubiquitination is taking place after recruitment to DNA, the question of how the recruitment to DNA is regulated remains open. Our objective is to study the role of FANCD2 phosphorylation in regulating recruitment to DNA and repair. We report a new cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits FANCD2 activation. Specifically, phosphorylation of FANCD2 in this cluster abrogates recruitment to ICLs and inhibits monoubiquitination in vitro and in vivo. Furthermore, phosphorylation of the cluster leads to a dramatic reduction in affinity of the FANCD2/FANCI complex towards DNA, which in turn blocks its monoubiquitination and the activation of the FA pathway. We describe a new regulatory mechanism where FANCD2 must be dephosphorylated prior to the loading of the FANCD2/FANCI complex onto DNA and activation of the FA pathway. This step could act as a safeguard against spurious activation of repair in the absence of damage.
Subjects/Keywords: 572; DNA repair; Genomic instability
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APA (6th Edition):
Lopez-Martinez, D. (2018). Characterisation of novel phosphorylation sites on FANCD2 and their role in the Fanconi anaemia pathway. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:1a749320-e434-41e3-8b5d-32c5481c0dee ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770584
Chicago Manual of Style (16th Edition):
Lopez-Martinez, David. “Characterisation of novel phosphorylation sites on FANCD2 and their role in the Fanconi anaemia pathway.” 2018. Doctoral Dissertation, University of Oxford. Accessed January 15, 2021.
http://ora.ox.ac.uk/objects/uuid:1a749320-e434-41e3-8b5d-32c5481c0dee ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770584.
MLA Handbook (7th Edition):
Lopez-Martinez, David. “Characterisation of novel phosphorylation sites on FANCD2 and their role in the Fanconi anaemia pathway.” 2018. Web. 15 Jan 2021.
Vancouver:
Lopez-Martinez D. Characterisation of novel phosphorylation sites on FANCD2 and their role in the Fanconi anaemia pathway. [Internet] [Doctoral dissertation]. University of Oxford; 2018. [cited 2021 Jan 15].
Available from: http://ora.ox.ac.uk/objects/uuid:1a749320-e434-41e3-8b5d-32c5481c0dee ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770584.
Council of Science Editors:
Lopez-Martinez D. Characterisation of novel phosphorylation sites on FANCD2 and their role in the Fanconi anaemia pathway. [Doctoral Dissertation]. University of Oxford; 2018. Available from: http://ora.ox.ac.uk/objects/uuid:1a749320-e434-41e3-8b5d-32c5481c0dee ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770584
Universiteit Utrecht
2.
Peeters, J.G.C.
Genetic instability: its causes and its consequences.
Degree: 2012, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/257555
► Alterations within the genome, referred to as genetic instability, can occur at the whole chromosome level, i.e. whole chromosomal instability (W-CIN), as well as at…
(more)
▼ Alterations within the genome, referred to as genetic
instability, can occur at the whole chromosome level, i.e. whole chromosomal
instability (W-CIN), as well as at the structural DNA level, i.e.
genomic instability and structural chromosomal
instability (S-CIN). Both types of genetic
instability are frequently observed in tumor cells and are causally related to tumor formation. Until recently, it was thought that the mechanisms underlying these two types of genetic
instability are distinct and occur independent of each other. However, several recent publications suggest that
instability at the whole chromosome level can be a driving force of structural
instability. This relationship between W-CIN and structural
instability sheds new light on the mechanisms by which W-CIN can contribute to tumorigenesis.
Advisors/Committee Members: Kops, G..
Subjects/Keywords: Whole chromosomal instability; genomic instability; structural chromosomal instability; cancer; tumorigenesis
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APA (6th Edition):
Peeters, J. G. C. (2012). Genetic instability: its causes and its consequences. (Masters Thesis). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/257555
Chicago Manual of Style (16th Edition):
Peeters, J G C. “Genetic instability: its causes and its consequences.” 2012. Masters Thesis, Universiteit Utrecht. Accessed January 15, 2021.
http://dspace.library.uu.nl:8080/handle/1874/257555.
MLA Handbook (7th Edition):
Peeters, J G C. “Genetic instability: its causes and its consequences.” 2012. Web. 15 Jan 2021.
Vancouver:
Peeters JGC. Genetic instability: its causes and its consequences. [Internet] [Masters thesis]. Universiteit Utrecht; 2012. [cited 2021 Jan 15].
Available from: http://dspace.library.uu.nl:8080/handle/1874/257555.
Council of Science Editors:
Peeters JGC. Genetic instability: its causes and its consequences. [Masters Thesis]. Universiteit Utrecht; 2012. Available from: http://dspace.library.uu.nl:8080/handle/1874/257555
University of California – Riverside
3.
Wang, Yehong.
Analysis of Heterochromatin-Associated Genomic Instability.
Degree: Environmental Toxicology, 2009, University of California – Riverside
URL: http://www.escholarship.org/uc/item/7kr0h1ds
► Heterochromatin represents special regions in the genome that have been found to be prone to breakage and rearrangements in cancer cells. Through two separate but…
(more)
▼ Heterochromatin represents special regions in the genome that have been found to be prone to breakage and rearrangements in cancer cells. Through two separate but related projects on heterochromatin, this dissertation demonstrates the important role of heterochromatin in maintaining genomic integrity. In the first project by transfecting non-coding heterochromatic sequences into cells, a significant increase in genomic instability was induced as demonstrated by increased Comet tails using the Comet assay. In the second project, we developed a more precise approach to measure the size of constitutive heterochromatin bands on human chromosomes. Using this new technique, we have seen increased variability of the heterochromatin regions of chromosomes 1 and 9 in lymphoblastoid cells derived from breast cancer patients as compared to that of age-matched controls. These results indicate that heteromorphisms in the heterochromatin of these chromosomes may be used as a biomarker to identify women with a higher susceptibility to breast cancer. In summary, these observations of heterochromatin- associated genomic instability suggest that heterochromatin regions are fragile sites for breakage and rearrangements and these alterations may act in a cis fashion to promote genomic instability.
Subjects/Keywords: Environmental Health; Biology, Genetics; Genomic Instability; Heterochromatin
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APA (6th Edition):
Wang, Y. (2009). Analysis of Heterochromatin-Associated Genomic Instability. (Thesis). University of California – Riverside. Retrieved from http://www.escholarship.org/uc/item/7kr0h1ds
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Wang, Yehong. “Analysis of Heterochromatin-Associated Genomic Instability.” 2009. Thesis, University of California – Riverside. Accessed January 15, 2021.
http://www.escholarship.org/uc/item/7kr0h1ds.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wang, Yehong. “Analysis of Heterochromatin-Associated Genomic Instability.” 2009. Web. 15 Jan 2021.
Vancouver:
Wang Y. Analysis of Heterochromatin-Associated Genomic Instability. [Internet] [Thesis]. University of California – Riverside; 2009. [cited 2021 Jan 15].
Available from: http://www.escholarship.org/uc/item/7kr0h1ds.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wang Y. Analysis of Heterochromatin-Associated Genomic Instability. [Thesis]. University of California – Riverside; 2009. Available from: http://www.escholarship.org/uc/item/7kr0h1ds
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Washington State University
4.
[No author].
Formation and Bypass of APOBEC-mediated DNA lesions
.
Degree: 2019, Washington State University
URL: http://hdl.handle.net/2376/17869
► AID/APOBEC family cytidine deaminases are established as endogenous DNA mutators that drive genomic instability in a wide array of human cancers. Many members of this…
(more)
▼ AID/APOBEC family cytidine deaminases are established as endogenous DNA mutators that drive
genomic instability in a wide array of human cancers. Many members of this family have a role in immunity through catalytically converting cytidines into uridines in single stranded DNA to increase immunoglobulin gene diversification or through hypermutation of viral intermediates. Recently DNA damage at trinucleotide motifs associated with APOBEC activity have come to spotlight as drivers of genetic
instability in a wide array of human cancers, with mutations manifesting as C to T and C to G base substitutions in TCW sequences. We assessed how these single stranded DNA-targeting enzymes damage double stranded chromosomal DNA, and how the mutagenic consequences of these lesions are avoided by expressing human APOBEC3A and APOBEC3B in a yeast model system. In these yeasts, we analyzed the mutation frequency of the CAN1 forward reporter gene as well as the genome-wide mutational pattern associated with either replicational or transcriptional strand biases. The results presented here demonstrate that these enzymes predominately damage single stranded DNA intermediates formed on the lagging-strand template during DNA replication, with minimal discernable contribution from lesions on transcription intermediates. As these lesions occur in single stranded DNA at the replication fork, they are bypassed in an error-free manner by a Rad51-mediated template switching pathway following lesion conversion from a deoxyuridine to a fork-stalling abasic ahead of the replicative polymerase, rather than through an excision repair mechanism. This suggests that the observed mutagenic burden in cancer cells may be understated if cancers cells are reliant upon similar mechanisms to mitigate APOBEC-mediated damage. Furthermore, the results strongly indicate that APOBEC-mediated DNA damage contributes to destabilizing
genomic integrity by generating mutations during DNA lagging-strand synthesis when bypass capacity is overwhelmed or incapacitated. A result of this could be the mutagenic activation of an oncogene or silencing of a tumor suppressor gene which could drive replication stress, exacerbating the mutagenic potential of APOBECs in a “perfect storm” of
genomic instability. Understanding how APOBEC mutations are generated can better shed light on how cancers are generated, diversify, and gain drug resistance which leads to tumor recurrence.
Advisors/Committee Members: Roberts, Steven A (advisor).
Subjects/Keywords: Molecular biology;
APOBEC;
Genomic instability;
Replication Fork
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APA ·
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Export
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Manager
APA (6th Edition):
author], [. (2019). Formation and Bypass of APOBEC-mediated DNA lesions
. (Thesis). Washington State University. Retrieved from http://hdl.handle.net/2376/17869
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
author], [No. “Formation and Bypass of APOBEC-mediated DNA lesions
.” 2019. Thesis, Washington State University. Accessed January 15, 2021.
http://hdl.handle.net/2376/17869.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
author], [No. “Formation and Bypass of APOBEC-mediated DNA lesions
.” 2019. Web. 15 Jan 2021.
Vancouver:
author] [. Formation and Bypass of APOBEC-mediated DNA lesions
. [Internet] [Thesis]. Washington State University; 2019. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/2376/17869.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
author] [. Formation and Bypass of APOBEC-mediated DNA lesions
. [Thesis]. Washington State University; 2019. Available from: http://hdl.handle.net/2376/17869
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Texas Southwestern Medical Center
5.
Torres, Michael Jason 1982-.
The Sec6/8 (a.k.a. Exocyst) Complex Supports DNA Repair Fidelity.
Degree: 2014, University of Texas Southwestern Medical Center
URL: http://hdl.handle.net/2152.5/3327
► The exocyst complex, first described in yeast, is a heterooctomeric complex that serves as a signaling platform to mediate cellular responses to diverse spatial and…
(more)
▼ The exocyst complex, first described in yeast, is a heterooctomeric complex that serves as a signaling platform to mediate cellular responses to diverse spatial and temporal cues. Evidence suggests that the exocyst might contribute to oncogenesis, potentially by disrupting spatial and temporal regulation of pathways critical to determining cell survival vs. apoptosis. Our work investigated how cancer cells subvert the exocyst to upregulate the AKT (v-akt murine thymoma viral oncogene) pro-survival pathway through the innate immune protein TBK1 (TANK-binding kinase 1). siRNA-mediated depletion of TBK1 in pancreatic and breast cancer cell lines results in apoptosis, which is mediated through the AKT pathway. Pharmacological inhibition of TBK1 recapitulates the apoptotic phenotype in mouse orthotopic models. Additionally, my work uncovered exocyst participation in the regulation of DNA repair. The isolation of multiple components of the DNA damage response (DDR) within the human exocyst protein-protein interaction network, together with the identification of Sec8 as a suppressor of the p53 response, prompted an investigation of functional interactions between the exocyst and the DDR. We found that exocyst perturbation resulted in a radioresistance phenotype to ionizing radiation (IR) that was associated with accelerated resolution of DNA damage. This occurred at the expense of
genomic integrity, as enhanced recombination frequencies correlated with the accumulation of aberrant chromatid exchanges. Exocyst-dependent modulation of the DDR is, at least in part, through restraint of the associated chromatin modifiers ATF2 and RNF20. Exocyst perturbation resulted in aberrant accumulation of ATF2 and RNF20; the promiscuous accumulation of DDR-associated chromatin marks; and IR-induced increased Rad51 repairosomes. Thus, the exocyst indirectly supports DNA repair fidelity by limiting formation of repair chromatin in the absence of a DNA damage signal. This newly revealed regulation of DNA repair by the exocyst may provide additional insight into the emerging observations of DNA damage protein involvement in pathways not canonically associated DNA repair, such as the host cytokinesis, host defense response, and maintenance of cilia. This work further substantiates the importance of the exocyst in normal cell biology and gives insight into how disruption of exocyst function can result in disease.
Advisors/Committee Members: Brekken, Rolf A., Cobb, Melanie H., Burma, Sandeep.
Subjects/Keywords: DNA Repair; Genomic Instability; Vesicular Transport Proteins
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APA (6th Edition):
Torres, M. J. 1. (2014). The Sec6/8 (a.k.a. Exocyst) Complex Supports DNA Repair Fidelity. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/3327
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Torres, Michael Jason 1982-. “The Sec6/8 (a.k.a. Exocyst) Complex Supports DNA Repair Fidelity.” 2014. Thesis, University of Texas Southwestern Medical Center. Accessed January 15, 2021.
http://hdl.handle.net/2152.5/3327.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Torres, Michael Jason 1982-. “The Sec6/8 (a.k.a. Exocyst) Complex Supports DNA Repair Fidelity.” 2014. Web. 15 Jan 2021.
Vancouver:
Torres MJ1. The Sec6/8 (a.k.a. Exocyst) Complex Supports DNA Repair Fidelity. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2014. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/2152.5/3327.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Torres MJ1. The Sec6/8 (a.k.a. Exocyst) Complex Supports DNA Repair Fidelity. [Thesis]. University of Texas Southwestern Medical Center; 2014. Available from: http://hdl.handle.net/2152.5/3327
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Queen Mary, University of London
6.
Worrall, Joseph Thomas.
Determining individual chromosome missegregation rates and the responses to aneuploidy in human cells.
Degree: PhD, 2018, Queen Mary, University of London
URL: http://qmro.qmul.ac.uk/xmlui/handle/123456789/31873
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.766098
► Genomic instability and aneuploidy, which are ubiquitous hallmarks of cancer cells, encompass both structural and numerical chromosome aberrations. Strikingly, cancer cells often display recurrent patterns…
(more)
▼ Genomic instability and aneuploidy, which are ubiquitous hallmarks of cancer cells, encompass both structural and numerical chromosome aberrations. Strikingly, cancer cells often display recurrent patterns of aneuploidy which are thought to be contingent on selection pressures within the tumour microenvironment maintaining advantageous karyotypes. However, it is currently unknown if individual chromosomes are intrinsically vulnerable to missegregation, and therefore whether chromosome bias may also contribute to pathological aneuploidy patterns. Moreover, the earliest responses to chromosome missegregation in non-transformed cells, and how these are overcome in cancer, has remained elusive due to the difficult nature of isolating nascent aneuploid cells. Results. Individual chromosomes displayed recurrent patterns of biased missegregation in response to a variety of cellular stresses across cell lines. Likewise, a small subset of chromosomes accounted for a large fraction of segregation errors following one specific mechanism driving aneuploidy. This was supported by the discovery that chromosomes 1 and 2 are strikingly susceptible to the premature loss of sister chromatid cohesion during prolonged prometaphase arrest. Additionally, I have elucidated the arrangement of individual metaphase human chromosomes, highlighting missegregation vulnerabilities occurring at the metaphase plate periphery following nocodazole wash-out. Finally, I have developed a novel system for isolating nascent aneuploid cells, suggesting the earliest transcriptome responses to chromosome missegregation in non-transformed human cells involve ATM and BCL2-mediated apoptosis.
Subjects/Keywords: Genomic instability; aneuploidy; cancer cells; chromosome missegregation
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APA ·
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APA (6th Edition):
Worrall, J. T. (2018). Determining individual chromosome missegregation rates and the responses to aneuploidy in human cells. (Doctoral Dissertation). Queen Mary, University of London. Retrieved from http://qmro.qmul.ac.uk/xmlui/handle/123456789/31873 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.766098
Chicago Manual of Style (16th Edition):
Worrall, Joseph Thomas. “Determining individual chromosome missegregation rates and the responses to aneuploidy in human cells.” 2018. Doctoral Dissertation, Queen Mary, University of London. Accessed January 15, 2021.
http://qmro.qmul.ac.uk/xmlui/handle/123456789/31873 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.766098.
MLA Handbook (7th Edition):
Worrall, Joseph Thomas. “Determining individual chromosome missegregation rates and the responses to aneuploidy in human cells.” 2018. Web. 15 Jan 2021.
Vancouver:
Worrall JT. Determining individual chromosome missegregation rates and the responses to aneuploidy in human cells. [Internet] [Doctoral dissertation]. Queen Mary, University of London; 2018. [cited 2021 Jan 15].
Available from: http://qmro.qmul.ac.uk/xmlui/handle/123456789/31873 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.766098.
Council of Science Editors:
Worrall JT. Determining individual chromosome missegregation rates and the responses to aneuploidy in human cells. [Doctoral Dissertation]. Queen Mary, University of London; 2018. Available from: http://qmro.qmul.ac.uk/xmlui/handle/123456789/31873 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.766098
Texas State University – San Marcos
7.
Banks, Kathryn Primrose.
The Function of ALYREF on UAP56-Mediated R-Loop Resolution.
Degree: MS, Biochemistry, 2020, Texas State University – San Marcos
URL: https://digital.library.txstate.edu/handle/10877/9886
► R-loops arise during transcription, and serve important roles including class switch recombination, protection of genes from DNA methylation at GC rich promoters, and promotion of…
(more)
▼ R-loops arise during transcription, and serve important roles including class switch recombination, protection of genes from DNA methylation at GC rich promoters, and promotion of transcription termination, but they can also cause replication stress and double-strand breaks if they are allowed to accumulate and are not resolved by the cell’s innate processes of R-loop resolution, which greatly contributes to
genomic instability. Cells do have methods of resolving persistent R-loops, but the mechanism of how these DNA replication and repair factors prevent R-loop accumulation remains unclear. Mutations in the TREX complex cause accumulation of co-transcriptional R-loops, and components of TREX, UAP56, and ALYREF, are of particular interest. UAP56 depletion in humans has been linked to a strong
genomic instability phenotype, demonstrated in part by preliminary unpublished data showing that depletion of UAP56 results in an increased level of R-loops in HeLa cells. ALYREF associates with UAP56, and has been found overexpressed in cancerous tissue. These implications prompt the exploration of the function of ALYREF on UAP56 mediated R-loop resolution activity. Our data provided proof that UAP56 has R-loop dissociation activity, emphasized that ALYREF had a direct effect on the DNA/RNA helicase and R-loop dissociation activities of UAP56, and explored the basis of interaction between the two proteins through ALYREF variants.
Advisors/Committee Members: Xue, Xiaoyu (advisor), Lewis, Karen (committee member), Lewis, L. K. (committee member).
Subjects/Keywords: R-loops; Genomic instability; ALYREF; UAP56; Genomics
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APA ·
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MLA ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Banks, K. P. (2020). The Function of ALYREF on UAP56-Mediated R-Loop Resolution. (Masters Thesis). Texas State University – San Marcos. Retrieved from https://digital.library.txstate.edu/handle/10877/9886
Chicago Manual of Style (16th Edition):
Banks, Kathryn Primrose. “The Function of ALYREF on UAP56-Mediated R-Loop Resolution.” 2020. Masters Thesis, Texas State University – San Marcos. Accessed January 15, 2021.
https://digital.library.txstate.edu/handle/10877/9886.
MLA Handbook (7th Edition):
Banks, Kathryn Primrose. “The Function of ALYREF on UAP56-Mediated R-Loop Resolution.” 2020. Web. 15 Jan 2021.
Vancouver:
Banks KP. The Function of ALYREF on UAP56-Mediated R-Loop Resolution. [Internet] [Masters thesis]. Texas State University – San Marcos; 2020. [cited 2021 Jan 15].
Available from: https://digital.library.txstate.edu/handle/10877/9886.
Council of Science Editors:
Banks KP. The Function of ALYREF on UAP56-Mediated R-Loop Resolution. [Masters Thesis]. Texas State University – San Marcos; 2020. Available from: https://digital.library.txstate.edu/handle/10877/9886
NSYSU
8.
Yeh, Yi-Jan.
Genomic instability in NSCLC detected by RAPD.
Degree: Master, Institute of Biomedical Sciences, 2001, NSYSU
URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0727101-155454
► Abstract Lung cancer is one of the most common cancer death in Taiwan. The dead population of lung cancer are over five thousands per year.…
(more)
▼ Abstract
Lung cancer is one of the most common cancer death in Taiwan. The dead population of lung cancer are over five thousands per year. High mortality and bad prognosis displayed the severity of the lung cancer. RAPD (Random Amplified Polymorphic DNA), a simple technique for the detection of
genomic instability, has been used in this research. We inquire into genetic variation in carcinogenesis, and find out genes association with NSCLC. Three or more than three DNA fragment patterns of normal and lung cancer samples exhibited by RAPD from the seven arbitrary were classified as
genomic instability. Four out of seven arbitrary primers have been used for lung cancer RAPD analysis and three of them were newly designed in this investigation. Analysis of
genomic instability with these seven random primers in twenty-seven NSCLC patients revealed that 81.48% of NSCLC exhibited
genomic instability.
The RAPD reproducibilities of primer 6 and primer 7 were the best among the seven primers used in this study. Therefore, the variable DNA fragments of primer 6 and primer 7 in RAPD analysis were subcloned and sequenced for the study of the possible mutated genes in NSCLC.
Results showed that DNA gains or losses were found in chromosomes 2, 4, 6, 14 and 22. After bioinformatic searching and alignments with human Genebank, some oncogenes (such as RABL2B, c-fos, n-myc and mas1)
and tumor suppressor gene (AR) were found located nearby the locus of
these subclones.
Genomic instability was investigated in relation with the clinical-pathological features such as age, stage, tumor size, metastasis, differential status, survival days and cancer types. Results, evaluated by the X2 test, were not significant except tumor stage.
Advisors/Committee Members: none (chair), none (committee member), none (chair).
Subjects/Keywords: NSCLC; Genomic instability; RAPD
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APA ·
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Manager
APA (6th Edition):
Yeh, Y. (2001). Genomic instability in NSCLC detected by RAPD. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0727101-155454
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Yeh, Yi-Jan. “Genomic instability in NSCLC detected by RAPD.” 2001. Thesis, NSYSU. Accessed January 15, 2021.
http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0727101-155454.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Yeh, Yi-Jan. “Genomic instability in NSCLC detected by RAPD.” 2001. Web. 15 Jan 2021.
Vancouver:
Yeh Y. Genomic instability in NSCLC detected by RAPD. [Internet] [Thesis]. NSYSU; 2001. [cited 2021 Jan 15].
Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0727101-155454.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Yeh Y. Genomic instability in NSCLC detected by RAPD. [Thesis]. NSYSU; 2001. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0727101-155454
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of California – Irvine
9.
Idica, Adam K.
miR-128 Directly Represses L1 Retrotransposition, Cellular Targets in L1 Retrotransposition and HIV-1 Replication.
Degree: Biological Sciences, 2016, University of California – Irvine
URL: http://www.escholarship.org/uc/item/80x871t6
► microRNAs (miRs) are small endogenously encoded RNAs that post-transcriptionally repress gene expression by degradation or translational repression of target mRNAs. miRs are involved in normal…
(more)
▼ microRNAs (miRs) are small endogenously encoded RNAs that post-transcriptionally repress gene expression by degradation or translational repression of target mRNAs. miRs are involved in normal development and homeostasis; dysregulation of miRs is tied to the development and progression of many diseases including cancer. Increasing evidence shows that miRs may have evolved to defend the human genome against mutagenesis by retroelements such as L1 retrotransposons or HIV-1. L1 retrotransposons account for approximately 17% of the human genome and are the only autonomous transposons that replicate by a copy-paste mechanism. L1 retrotransposition is associated with mutagenesis and genomic instability, two factors implicated in cancer and various genetic disorders. HIV-1 is a retrovirus that infects millions of people worldwide and can lead to fatal acquired immune deficiency syndrome (AIDS). Current anti-retroviral therapies are effective at reducing viral loads to non-detectable levels and prolonging the lifespan of patients; however, HIV-1 may remain latent in the genome and can be reactivated later. The focus of this dissertation is to elucidate the mechanisms of miR-128-mediated repression of L1, its repression of cellular TNPO1 and hnRNP A1 that are involved in L1 retrotransposition, as well as cellular TNPO3 involved in HIV-1 replication. We identify a novel miR, miR-128, involved in L1 retrotransposition. We demonstrate that miR-128 represses L1 RNA, protein, and de novo retrotransposition by a direct binding mechanism in multiple cell lines including cancer initiating cells and induced pluripotent stem cells (iPSCs) (Chapter 2). miRs are highly pleiotropic with a single miR targeting multiple mRNAs in the same pathway. We show that TNPO1 is a cellular target of miR-128, and is necessary for efficient replication of L1 retrotransposons and nuclear import of L1 ORF1p (Chapter 3). We provide evidence that hnRNP A1 is also a direct target of miR-128 and repression of hnRNP A1 significantly reduces L1 RNA, protein and de novo L1 retrotransposition (Chapter 4). Lastly, we identify TNPO3 which is known to be involved in HIV-1 replication as a direct target of miR-128. Reduction of TNPO3 by miR-128 over-expression significantly reduces HIV-1 replication using a single cycle HIV-1 luciferase reporter virus (Chapter 5).
Subjects/Keywords: Molecular biology; Biochemistry; genomic instability; HIV-1; LINE-1; microRNA; Retrotransposon
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APA (6th Edition):
Idica, A. K. (2016). miR-128 Directly Represses L1 Retrotransposition, Cellular Targets in L1 Retrotransposition and HIV-1 Replication. (Thesis). University of California – Irvine. Retrieved from http://www.escholarship.org/uc/item/80x871t6
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Idica, Adam K. “miR-128 Directly Represses L1 Retrotransposition, Cellular Targets in L1 Retrotransposition and HIV-1 Replication.” 2016. Thesis, University of California – Irvine. Accessed January 15, 2021.
http://www.escholarship.org/uc/item/80x871t6.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Idica, Adam K. “miR-128 Directly Represses L1 Retrotransposition, Cellular Targets in L1 Retrotransposition and HIV-1 Replication.” 2016. Web. 15 Jan 2021.
Vancouver:
Idica AK. miR-128 Directly Represses L1 Retrotransposition, Cellular Targets in L1 Retrotransposition and HIV-1 Replication. [Internet] [Thesis]. University of California – Irvine; 2016. [cited 2021 Jan 15].
Available from: http://www.escholarship.org/uc/item/80x871t6.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Idica AK. miR-128 Directly Represses L1 Retrotransposition, Cellular Targets in L1 Retrotransposition and HIV-1 Replication. [Thesis]. University of California – Irvine; 2016. Available from: http://www.escholarship.org/uc/item/80x871t6
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
10.
Puccetti, Matthew Vincent.
The role of DNA replication fork remodeling proteins in lymphomagenesis and hematopoietic cell replication stress.
Degree: PhD, Pathology, 2018, Vanderbilt University
URL: http://hdl.handle.net/1803/15446
► Genome maintenance is essential for the viability of eukaryotic cells and for the prevention of tumorigenesis. DNA replication stress is a significant contributor to genomic…
(more)
▼ Genome maintenance is essential for the viability of eukaryotic cells and for the prevention of tumorigenesis. DNA replication stress is a significant contributor to
genomic instability. As such, cells employ a complex replication stress response to prevent replication fork collapse upon experiencing DNA replication stress. In this dissertation, I evaluated the roles of the closely related replication fork remodeling proteins Smarcal1 and Zranb3 in lymphomagenesis. With genetic mouse models, I showed these proteins function by stabilizing replication forks in vivo in response to multiple replication stress-inducing stimuli, and determined their loss greatly impacts tumor development phenotypes. Specifically, loss of Smarcal1 significantly increased susceptibility to γ-radiation-induced replication stress and delayed T-cell lymphoma formation in vivo. This phenotype was due to elevated sensitivity to replication stress in Smarcal1-deficient hematopoietic stem cells, as evidenced by increased DNA damage and apoptosis of these cells during forced proliferation. Moreover, by utilizing the Eµ-myc B-cell lymphoma mouse model, I determined that Smarcal1 and Zranb3 are essential for stabilizing replication forks during oncogenic stress, and that they do so in a non-redundant fashion. Loss of one or both alleles of either protein resulted in distinct alterations in lymphoma formation, replication fork stability, DNA damage accumulation and apoptosis, depending on whether one, two or no alleles of either protein were expressed. These data are the first to directly link both Smarcal1 and Zranb3 to the cellular response to replication stress in vivo and identify Myc as the first endogenous source of replication stress that requires both proteins for resolution. Moreover, these data provide mechanistic insight into how replication stress and fork remodeling proteins influence cancer development and establish two novel proteins as significant contributors to hematologic malignancies.
Advisors/Committee Members: Deborah Lannigan, Ph.D. (committee member), Christine Eischen, P.D. (committee member), William Tansey, Ph.D. (committee member), David Cortez, Ph.D. (committee member), Larry Swift, Ph.D. (Committee Chair).
Subjects/Keywords: DNA translocases; DNA damage response; genomic instability; replication fork remodeling; tumorigenesis
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APA ·
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APA (6th Edition):
Puccetti, M. V. (2018). The role of DNA replication fork remodeling proteins in lymphomagenesis and hematopoietic cell replication stress. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15446
Chicago Manual of Style (16th Edition):
Puccetti, Matthew Vincent. “The role of DNA replication fork remodeling proteins in lymphomagenesis and hematopoietic cell replication stress.” 2018. Doctoral Dissertation, Vanderbilt University. Accessed January 15, 2021.
http://hdl.handle.net/1803/15446.
MLA Handbook (7th Edition):
Puccetti, Matthew Vincent. “The role of DNA replication fork remodeling proteins in lymphomagenesis and hematopoietic cell replication stress.” 2018. Web. 15 Jan 2021.
Vancouver:
Puccetti MV. The role of DNA replication fork remodeling proteins in lymphomagenesis and hematopoietic cell replication stress. [Internet] [Doctoral dissertation]. Vanderbilt University; 2018. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1803/15446.
Council of Science Editors:
Puccetti MV. The role of DNA replication fork remodeling proteins in lymphomagenesis and hematopoietic cell replication stress. [Doctoral Dissertation]. Vanderbilt University; 2018. Available from: http://hdl.handle.net/1803/15446
Penn State University
11.
Choe, Katherine Naeun.
HUWE1 Interacts with PCNA to Alleviate Replication Stress.
Degree: 2016, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/13492kzc152
► The integrity of the genome relies on the accurate and faithful duplication of genetic information from a parental cell to its progeny during each cellular…
(more)
▼ The integrity of the genome relies on the accurate and faithful duplication of genetic information from a parental cell to its progeny during each cellular division. Defects in DNA replication, DNA damage response, or DNA repair compromise
genomic stability and promote cancer development as well as other diseases. In particular, unrepaired DNA lesions can arrest the progression of the DNA replication machinery during S-phase, causing replication stress, mutations, and DNA breaks. HUWE1 is a HECT-type ubiquitin ligase that targets proteins involved in cell fate, survival and differentiation. Here, we report that HUWE1 is essential for
genomic stability, by promoting replication of damaged DNA. We show that HUWE1-knockout cells are unable to mitigate replication stress, resulting in replication defects and DNA breakage. Importantly, we find that this novel role of HUWE1 requires its interaction with the replication factor PCNA, a master regulator of replication fork restart, at stalled replication forks. Finally, we provide evidence that HUWE1 monoubiquitinates H2AX to promote signaling at stalled forks. Altogether, our work identifies HUWE1 as a novel regulator of the replication stress response.
Advisors/Committee Members: George Lucian Moldovan, Dissertation Advisor/Co-Advisor, George Lucian Moldovan, Committee Chair/Co-Chair, James Riley Broach, Committee Member, Ralph Lauren Keil, Committee Member, Kent Eugene Vrana, Outside Member, Cristina I Truica, Special Member.
Subjects/Keywords: DNA replication; Genomic instability; H2AX; DNA Damage; HUWE1; PCNA; Replication stress
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APA ·
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CSE |
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APA (6th Edition):
Choe, K. N. (2016). HUWE1 Interacts with PCNA to Alleviate Replication Stress. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13492kzc152
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Choe, Katherine Naeun. “HUWE1 Interacts with PCNA to Alleviate Replication Stress.” 2016. Thesis, Penn State University. Accessed January 15, 2021.
https://submit-etda.libraries.psu.edu/catalog/13492kzc152.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Choe, Katherine Naeun. “HUWE1 Interacts with PCNA to Alleviate Replication Stress.” 2016. Web. 15 Jan 2021.
Vancouver:
Choe KN. HUWE1 Interacts with PCNA to Alleviate Replication Stress. [Internet] [Thesis]. Penn State University; 2016. [cited 2021 Jan 15].
Available from: https://submit-etda.libraries.psu.edu/catalog/13492kzc152.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Choe KN. HUWE1 Interacts with PCNA to Alleviate Replication Stress. [Thesis]. Penn State University; 2016. Available from: https://submit-etda.libraries.psu.edu/catalog/13492kzc152
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
12.
A. Colosio.
MECHANISMS MEDIATING REPLICATION FORK COLLAPSE AND PROCESSING IN CHECKPOINT DEFECTIVE CELLS.
Degree: 2014, Università degli Studi di Milano
URL: http://hdl.handle.net/2434/234147
► ABSTRACT An accurate DNA replication is essential to prevent genome instability events, such as mutations and chromosomal rearrangements that are hallmarks of neoplastic transformation and…
(more)
▼ ABSTRACT
An accurate DNA replication is essential to prevent genome
instability events, such as mutations and chromosomal rearrangements that are hallmarks of neoplastic transformation and cancer onset. A dedicated branch of the DNA damage checkpoint maintains the integrity of replicating chromosomes by stabilising replication forks in the presence of genotoxic agents, thus ensuring cell viability. Upon fork collapse, budding yeast checkpoint mutants experiencing replication stress accumulate aberrant replication intermediates, such as gapped and hemireplicated molecules, as well as four-branched structures known as reversed forks. Aberrant replication intermediates are potentially harmful for the cells since they are thought to trigger unscheduled recombination events that cause genome rearrangements. In this PhD thesis, I examined checkpoint-dependent mechanisms controlling fork stability, and I provide in vivo evidence that positive supercoiling accumulating ahead of replication forks is the main mechanical force driving fork reversal. Thus, DNA topology is a critical determinant of replication fork stability in vivo. Furthermore, a 2D-gel screening for enzymatic activities involved in the metabolism of collapsed forks, revealed a novel role for the Sae2 and Dna2 endonucelases in replication intermediates processing.
Advisors/Committee Members: supervisor: M. Foiani, added supervisor: R. Bermejo, FOIANI, MARCO, FOIANI, MARCO.
Subjects/Keywords: genomic instability; cell cycle checkpoint; DNA repair; Settore BIO/10 - Biochimica
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APA (6th Edition):
Colosio, A. (2014). MECHANISMS MEDIATING REPLICATION FORK COLLAPSE AND PROCESSING IN CHECKPOINT DEFECTIVE CELLS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/234147
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Colosio, A.. “MECHANISMS MEDIATING REPLICATION FORK COLLAPSE AND PROCESSING IN CHECKPOINT DEFECTIVE CELLS.” 2014. Thesis, Università degli Studi di Milano. Accessed January 15, 2021.
http://hdl.handle.net/2434/234147.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Colosio, A.. “MECHANISMS MEDIATING REPLICATION FORK COLLAPSE AND PROCESSING IN CHECKPOINT DEFECTIVE CELLS.” 2014. Web. 15 Jan 2021.
Vancouver:
Colosio A. MECHANISMS MEDIATING REPLICATION FORK COLLAPSE AND PROCESSING IN CHECKPOINT DEFECTIVE CELLS. [Internet] [Thesis]. Università degli Studi di Milano; 2014. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/2434/234147.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Colosio A. MECHANISMS MEDIATING REPLICATION FORK COLLAPSE AND PROCESSING IN CHECKPOINT DEFECTIVE CELLS. [Thesis]. Università degli Studi di Milano; 2014. Available from: http://hdl.handle.net/2434/234147
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
13.
Bianco, Julien.
Rôle du complexe Claspine-Timeless-Tipin dans le maintien de la stabilité du génome au cours de la réplication : Role of Claspine-Timeless-Tipin complex in genome stability maintenance during replication.
Degree: Docteur es, Biologie Santé, 2010, Université Montpellier I
URL: http://www.theses.fr/2010MON1T009
► Il a été montré récemment que l'instabilité génétique joue un rôle central dans les étapes précoces de la tumorigenèse. Celle-ci provoquerait une activation chronique des…
(more)
▼ Il a été montré récemment que l'instabilité génétique joue un rôle central dans les étapes précoces de la tumorigenèse. Celle-ci provoquerait une activation chronique des voies ATR/CHK1 et ATM/CHK2 dans les cellules précancéreuses, entrainant l'apoptose ou la sénescence des cellules concernées. Les mécanismes de checkpoint constituant une barrière contre la progression tumorale, toute mutation affectant ce checkpoint serait ainsi sélectionnée très tôt dans le processu s de tumorigenèse et faciliterait ensuite la progression tumorale. Ce modèle met en évidence le rôle central de l'instabilité génomique et du checkpoint dans la progression tumorale.Au cours de ma thèse, je me suis intéressé au complexe Claspine / Timeless / Tipin, initialement identifié comme médiateur de la voie ATR/CHK1 et qui est donc considéré comme ayant une fonction suppresseur de tumeur. Cependant, Claspine présente aussi des propriétés oncogéniques, puisque qu'elle est surexprimée dans de nombreuses lignées tumorales et cette surexpression est importante pour la prolifération cellulaire. Nous nous sommes donc demandé comment cette protéine pouvait être à la fois un oncogène et un suppresseur de tumeur. Chez la levure, l'homologue de Claspine est impliqué dans le maintien de la stabilité des fourches de réplication, indépendamment de sa fonction dans le checkpoint. Nous proposons que dans les cellules cancéreuses cette surexpression permette une meilleure stabilité des fourches, ce qui serait très important pour répliquer efficacement un génome soumis à un stress réplicatif constant. Au cours de ma thèse, nous avons construit et caractérisé un modèle de cellulescancéreuses HCT116 dans lesquelles nous avons diminué le niveau de Claspine ou deTimeless grâce à des shRNA, sans que cela n'affecte l'efficacité du checkpoint de réplication. Nous avons pu observer dans ces cellules un ralentissement de la progression des fourches de réplication et l'apparition d'une instabilité génétique. Il semblerait que spécifiquement dans le cas de Timeless, le ralentissement de la fourche de réplication et l'instabilité génomique se manifeste surtout dans les régions du génome répliquées tardivement.
The correct execution of the replication program is essential for the maintenance of genome integrity during S phase. Indeed, replication fork progression is frequently challenged by DNA lesions and by a variety of natural pause sites. Arrested forks are unstable structures, which represent a major threat for the genome integrity if they are not promptly stabilized and restarted. In response to replicative stress, cells activated the replication checkpoint to prevent collapse of stalled forks and promote fork recovery. Recent evidence indicates that spontaneous replication stress occurs in precancerous lesions and promotes the development of cancer. Identifying the origin of this replication stress would represent a better understanding of the early stages of tumorigenesis. We study the function of Claspin, a mediator of the replication checkpoint, which plays a key…
Advisors/Committee Members: Pasero, Philippe (thesis director), Tourrière, Hélène (thesis director).
Subjects/Keywords: Replication; Checkpoint; Instabilité génomique; Replication; Checkpoint; Genomic instability
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APA ·
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Export
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APA (6th Edition):
Bianco, J. (2010). Rôle du complexe Claspine-Timeless-Tipin dans le maintien de la stabilité du génome au cours de la réplication : Role of Claspine-Timeless-Tipin complex in genome stability maintenance during replication. (Doctoral Dissertation). Université Montpellier I. Retrieved from http://www.theses.fr/2010MON1T009
Chicago Manual of Style (16th Edition):
Bianco, Julien. “Rôle du complexe Claspine-Timeless-Tipin dans le maintien de la stabilité du génome au cours de la réplication : Role of Claspine-Timeless-Tipin complex in genome stability maintenance during replication.” 2010. Doctoral Dissertation, Université Montpellier I. Accessed January 15, 2021.
http://www.theses.fr/2010MON1T009.
MLA Handbook (7th Edition):
Bianco, Julien. “Rôle du complexe Claspine-Timeless-Tipin dans le maintien de la stabilité du génome au cours de la réplication : Role of Claspine-Timeless-Tipin complex in genome stability maintenance during replication.” 2010. Web. 15 Jan 2021.
Vancouver:
Bianco J. Rôle du complexe Claspine-Timeless-Tipin dans le maintien de la stabilité du génome au cours de la réplication : Role of Claspine-Timeless-Tipin complex in genome stability maintenance during replication. [Internet] [Doctoral dissertation]. Université Montpellier I; 2010. [cited 2021 Jan 15].
Available from: http://www.theses.fr/2010MON1T009.
Council of Science Editors:
Bianco J. Rôle du complexe Claspine-Timeless-Tipin dans le maintien de la stabilité du génome au cours de la réplication : Role of Claspine-Timeless-Tipin complex in genome stability maintenance during replication. [Doctoral Dissertation]. Université Montpellier I; 2010. Available from: http://www.theses.fr/2010MON1T009
University of Adelaide
14.
Puccini, Joseph.
Characterisation of caspase-2 function in the DNA damage response and tumour suppression.
Degree: 2014, University of Adelaide
URL: http://hdl.handle.net/2440/93503
► Caspases are a family of cysteine proteases that have essential functions in the regulation of apoptosis and inflammation. Despite being the most evolutionarily conserved caspase,…
(more)
▼ Caspases are a family of cysteine proteases that have essential functions in the regulation of apoptosis and inflammation. Despite being the most evolutionarily conserved caspase, the physiological functions of caspase-2 remain poorly defined. This is partly because caspase-2 knockout (Casp2⁻ʹ⁻) mice show no overt phenotype and only limited, tissue-specific apoptotic defects. Previous work from our laboratory has provided the first direct evidence demonstrating a role for caspase-2 in tumour suppression and protection against cellular transformation. However, the molecular mechanisms by which caspase-2 exerts these functions were not clearly defined. In order to characterise the tumour suppressor function of caspase-2, the processes and pathways disrupted in caspase-2-deficient cells were investigated. Analysis of serially-passaged mouse embryonic fibroblasts (MEFs) demonstrated that caspase-2-deficiency promoted escape from replicative senescence which coincided with impaired induction of cyclin-dependent kinase inhibitors. Consistent with the increased proliferation rate of primary Casp2⁻ʹ⁻ MEFs, spontaneously-immortalized Casp2⁻ʹ⁻ MEFs that had escaped replicative senescence also displayed an enhanced proliferative capacity compared to their wild type counterparts. These findings suggest that caspase-2 regulates cell proliferation which may contribute to its ability to protect against cellular transformation. Furthermore, serially-passaged Casp2⁻ʹ⁻ primary MEFs and Eμ-Myc/Casp2⁻ʹ⁻ lymphomas showed enhanced aneuploidy, demonstrating that loss of caspase-2 promotes
genomic instability (GIN). Treatment of Casp2⁻ʹ⁻ MEFs with ionizing radiation (IR) resulted in persistent DNA damage and defective cell cycle checkpoint regulation, suggesting that caspase-2-deficient cells have an impaired ability to efficiently respond to and repair DNA damage. Further analysis revealed that caspase‐2‐deficient MEFs and Eμ-Myc lymphomas displayed defective activation of p53 and its downstream targets following IR treatment. Therefore, an attenuated p53 response may contribute to defective DNA damage response (DDR) signalling and GIN in caspase-2-deficient cells. In order to further investigate the extent and specificity of caspase-2 function in tumour suppression using an independent tumour model, Atm⁺ʹ⁻ and Casp2⁻ʹ⁻ mice were inter-crossed to generate Atm⁻ʹ⁻Casp2⁻ʹ⁻ mice. Initial characterization revealed that caspase-2-deficiency enhanced growth retardation and caused perinatal lethality in Atm⁻ʹ⁻ mice. A comparison of tumour susceptibility demonstrated that Atm⁻ʹ⁻Casp2⁻ʹ⁻ mice developed lymphomas with a dramatically increased onset and penetrance compared to Atm⁻ʹ⁻ mice, providing additional evidence supporting a tumour suppressor function for caspase-2. Furthermore, Atm⁻ʹ⁻Casp2⁻ʹ⁻ lymphomas showed an increased proliferation rate and enhanced oxidative damage compared to Atm⁻ʹ⁻ lymphomas. Moreover, lymphomas and pre-malignant lymphocytes derived from Atm⁻ʹ⁻Casp2⁻ʹ⁻ mice displayed enhanced aneuploidy, linking the function of…
Advisors/Committee Members: Kumar, Sharad (advisor), Dorstyn, Loretta Esterina (advisor), School of Medicine (school).
Subjects/Keywords: cancer; tumour suppression; DNA damage response; caspases; genomic instability; cell cycle
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APA ·
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MLA ·
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Export
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APA (6th Edition):
Puccini, J. (2014). Characterisation of caspase-2 function in the DNA damage response and tumour suppression. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/93503
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Puccini, Joseph. “Characterisation of caspase-2 function in the DNA damage response and tumour suppression.” 2014. Thesis, University of Adelaide. Accessed January 15, 2021.
http://hdl.handle.net/2440/93503.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Puccini, Joseph. “Characterisation of caspase-2 function in the DNA damage response and tumour suppression.” 2014. Web. 15 Jan 2021.
Vancouver:
Puccini J. Characterisation of caspase-2 function in the DNA damage response and tumour suppression. [Internet] [Thesis]. University of Adelaide; 2014. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/2440/93503.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Puccini J. Characterisation of caspase-2 function in the DNA damage response and tumour suppression. [Thesis]. University of Adelaide; 2014. Available from: http://hdl.handle.net/2440/93503
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Univerzitet u Beogradu
15.
Čabarkapa, Andrea M., 1985-.
Uticaj etanolnog ekstrakta lista masline (Olea europaea
L.) na genomsku nestabilnost, parametre oksidativnog stresa i
inflamacije kod pacijenata sa reumatoidnim artritisom.
Degree: Biološki fakultet, 2017, Univerzitet u Beogradu
URL: https://fedorabg.bg.ac.rs/fedora/get/o:14398/bdef:Content/get
► Biologija - Genetika / Biology - Genetics
Reumatoidni artritis (RA) predstavlja autoimunsko inflamatorno oboljenje, u čijem razvoju ključnu ulogu imaju inflamatorni medijatori i oksidativni stres,…
(more)
▼ Biologija - Genetika / Biology -
Genetics
Reumatoidni artritis (RA) predstavlja autoimunsko
inflamatorno oboljenje, u čijem razvoju ključnu ulogu imaju
inflamatorni medijatori i oksidativni stres, koji mogu dovesti do
oštećenja biomolekula i nastanka genomske nestabilnosti. Suvi
etanolni ekstrakt lista masline (engl. dry olive leaf extract,
DOLE) je poznat po izuzetnim antioksidativnim, antiinflamatornim i
genoprotektivnim dejstvima. Međutim, do sada nisu ispitivani
njegovi efekti u terapiji RA. Cilj istraživanja ove doktorske
disertacije je poređenje efekata tronedeljne i šestonedeljne
kombinovane terapije metotreksatom i DOLE u odnosu na efekte
standardne terapije samo metotreksatom, kod pacijenata sa RA. U
istraživanju je učestvovalo 8 pacijenata novodijagnostikovanih za
RA, 16 pacijenata sa dugotrajnim RA, koji su bili na kombinovanoj
terapiji, dok je posebnu grupu činilo 8 novodijagnostikovanih
pacijenata na terapiji samo metotreksatom. Kod sve tri grupe, pre
uvođenja eksperimentalne terapije, zabeležen je povišen nivo
inflamacije, oksidativnih oštećenja lipida, proteina i DNK, kao i
povećana učestalost mikronukleusa u odnosu na vrednosti kod zdravih
kontrolnih ispitanika. Rezultati tronedeljne i šestonedeljne
terapije su pokazali da kombinovana primena DOLE i metotreksata
daje bolje efekte u odnosu na terapiju samo metotreksatom, pre
svega u pogledu efikasnije redukcije primarnih DNK oštećenja, kao i
redukcije nivoa interleukina-6, kod pacijenata u ranoj fazi RA.
Kombinovana terapija je takođe pokazala efekat u redukciji nitrita
kod grupe u ranoj fazi RA i smanjenje lipidne peroksidacije kod
dugotrajno obolelih pacijenata. Praćenjem učestalosti mikronukleusa
u limfocitima, nisu utvrđeni značajni efekti terapije na nivo
genomske nestabilnosti posle šest nedelja.Pokazani su pozitivni
efekti kombinovane terapijske primene metotreksata i DOLE na
oksidativna oštećenja ćelija kod pacijenata u ranoj fazi RA, u
poređenju sa terapijom samo metotreksatom. Kombinovana terapija je
bila efikasnija u ranoj fazi RA, dok su njeni efekti slabije
izraženi kod dugotrajnog stanja aktivne bolesti.
Advisors/Committee Members: Potparević, Biljana, 1966-.
Subjects/Keywords: rheumatoid arthritis; olive leaf extract; oxidative
stress; genomic instability; inflammation;
antioxidants
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APA (6th Edition):
Čabarkapa, Andrea M., 1. (2017). Uticaj etanolnog ekstrakta lista masline (Olea europaea
L.) na genomsku nestabilnost, parametre oksidativnog stresa i
inflamacije kod pacijenata sa reumatoidnim artritisom. (Thesis). Univerzitet u Beogradu. Retrieved from https://fedorabg.bg.ac.rs/fedora/get/o:14398/bdef:Content/get
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Čabarkapa, Andrea M., 1985-. “Uticaj etanolnog ekstrakta lista masline (Olea europaea
L.) na genomsku nestabilnost, parametre oksidativnog stresa i
inflamacije kod pacijenata sa reumatoidnim artritisom.” 2017. Thesis, Univerzitet u Beogradu. Accessed January 15, 2021.
https://fedorabg.bg.ac.rs/fedora/get/o:14398/bdef:Content/get.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Čabarkapa, Andrea M., 1985-. “Uticaj etanolnog ekstrakta lista masline (Olea europaea
L.) na genomsku nestabilnost, parametre oksidativnog stresa i
inflamacije kod pacijenata sa reumatoidnim artritisom.” 2017. Web. 15 Jan 2021.
Vancouver:
Čabarkapa, Andrea M. 1. Uticaj etanolnog ekstrakta lista masline (Olea europaea
L.) na genomsku nestabilnost, parametre oksidativnog stresa i
inflamacije kod pacijenata sa reumatoidnim artritisom. [Internet] [Thesis]. Univerzitet u Beogradu; 2017. [cited 2021 Jan 15].
Available from: https://fedorabg.bg.ac.rs/fedora/get/o:14398/bdef:Content/get.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Čabarkapa, Andrea M. 1. Uticaj etanolnog ekstrakta lista masline (Olea europaea
L.) na genomsku nestabilnost, parametre oksidativnog stresa i
inflamacije kod pacijenata sa reumatoidnim artritisom. [Thesis]. Univerzitet u Beogradu; 2017. Available from: https://fedorabg.bg.ac.rs/fedora/get/o:14398/bdef:Content/get
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of California – San Francisco
16.
Finn, Kenneth John.
Re-Replication Induced Gene Amplification: Phenomenon, Mechanism, and Significance.
Degree: Biochemistry and Molecular Biology, 2013, University of California – San Francisco
URL: http://www.escholarship.org/uc/item/85w067p6
► Eukaryotic cells employ a battery of overlapping control mechanisms to ensure that each segment of their genome is replicated once, and only once, per cell…
(more)
▼ Eukaryotic cells employ a battery of overlapping control mechanisms to ensure that each segment of their genome is replicated once, and only once, per cell cycle. While the long standing view of the field is that this tight block to re-replication is necessary for the preservation of genome integrity, there is no direct experimental evidence supporting this belief. The work presented in Chapter 2 critically evaluates this idea and demonstrates that experimental induction of low, sub-lethal levels of re-replication in Saccharomyces cerevisiae can indeed cause at least one form of genomic instability, namely gene amplification. The mechanism of such Re-Replication Induced Gene Amplification (RRIGA) is explored in Chapter 3. There, I show that re-replication forks are prone to frequent breakage, which instigates a repair response. Non-allelic repetitive sequence elements positioned to either side of the re-initiating origin undergo homologous recombination through a single-stranded annealing mechanism, ultimately generating a head-to-tail duplication in loco. These duplications have repetitive sequence elements at the amplicon boundaries and a hybrid repetitive element at the inter-amplicon junction. The details of the mechanism provide insight into why re-replication is so efficient at producing segmental amplifications. Finally, in Chapter 4 I address the relevance of RRIGA. There I present evidence that RRIGA is a likely driver of spontaneous segmental amplifications in cells with intact replication controls. Furthermore, I show that very slight disruption of replication control greatly increases the rate of such amplifications. These findings strongly suggest a role for RRIGA in both evolution and oncogenesis.
Subjects/Keywords: Molecular biology; Evolution; Gene Amplification; Genomic Instability; Oncogenesis; Replication; Re-Replication
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APA (6th Edition):
Finn, K. J. (2013). Re-Replication Induced Gene Amplification: Phenomenon, Mechanism, and Significance. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/85w067p6
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Finn, Kenneth John. “Re-Replication Induced Gene Amplification: Phenomenon, Mechanism, and Significance.” 2013. Thesis, University of California – San Francisco. Accessed January 15, 2021.
http://www.escholarship.org/uc/item/85w067p6.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Finn, Kenneth John. “Re-Replication Induced Gene Amplification: Phenomenon, Mechanism, and Significance.” 2013. Web. 15 Jan 2021.
Vancouver:
Finn KJ. Re-Replication Induced Gene Amplification: Phenomenon, Mechanism, and Significance. [Internet] [Thesis]. University of California – San Francisco; 2013. [cited 2021 Jan 15].
Available from: http://www.escholarship.org/uc/item/85w067p6.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Finn KJ. Re-Replication Induced Gene Amplification: Phenomenon, Mechanism, and Significance. [Thesis]. University of California – San Francisco; 2013. Available from: http://www.escholarship.org/uc/item/85w067p6
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of California – San Francisco
17.
Richardson, Christopher Douglas.
Re-Initiation Promoters: Genetic Elements that Modify Cell Cycle Control of Adjacent DNA Replication Origins.
Degree: Biochemistry and Molecular Biology, 2014, University of California – San Francisco
URL: http://www.escholarship.org/uc/item/2qg774vw
► Replication control is fundamental to genomic stability as aberrant replication within a single cell cycle can induce high rates of segmental amplification, chromosomal aneuploidy, and…
(more)
▼ Replication control is fundamental to genomic stability as aberrant replication within a single cell cycle can induce high rates of segmental amplification, chromosomal aneuploidy, and possibly other genomic instabilities. Current models for how eukaryotic cells prevent such re-initiation focus on the global cell-wide inhibition of replication proteins involved in loading the Mcm2-7 replicative helicase at origins (e.g. cyclin dependent kinase, CDK, inhibition of ORC, Cdc6, Cdt1, Mcm2-7). By preventing this initial step of initiation from reoccurring once S phase begins, re-initiation can be effectively prevented. Such models, however, treat origins as generic interchangeable elements and cannot account for the diverse efficiencies with which origins re-initiate when global control mechanisms are disrupted. These varied re-initiation efficiencies also cannot be explained by the well-documented diversity in origin timing and efficiency observed during normal S phase initiation. Instead, we now have evidence of a novel mechanism that contributes to the diversity in origin re-initiation efficiency.Chapter 2 of this dissertation details the identification and characterization of genetic elements near ARS317 and ARS1238 that confer preferential re-replication on these and other origins when cell cycle control of MCM2-7 and Cdc6 is disrupted. These elements do not confer any detectable change on the replication efficiency or timing of adjacent origins, suggesting that their regulatory effect is specific to origin re-initiation. Hence, we refer to these elements as Re-Initiation Promoters (RIPs). The two RIPs mapped are AT rich sequences 40-50bp in size and exert their effects on adjacent origins in an orientation and distance dependent manner. Analysis of Mcm2-7 association with origins suggests that RIP elements allow local escape from the residual CDK inhibition of helicase loading when global CDK inhibition of Mcm2-7 and Cdc6 is disrupted. Such local modulation of origin control suggests that there is a complex genomic landscape of re-replication potential, particularly when mechanisms preventing re-replication are partially or sporadically disrupted. Hence, if re-replication does contribute to genomic alterations, as has been speculated for cancer cells, some regions of the genome may be more susceptible to these alterations than others.
Subjects/Keywords: Biochemistry; Molecular biology; DNA; Genomic Instability; Local Control; Replication; Re-replication
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APA (6th Edition):
Richardson, C. D. (2014). Re-Initiation Promoters: Genetic Elements that Modify Cell Cycle Control of Adjacent DNA Replication Origins. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/2qg774vw
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Richardson, Christopher Douglas. “Re-Initiation Promoters: Genetic Elements that Modify Cell Cycle Control of Adjacent DNA Replication Origins.” 2014. Thesis, University of California – San Francisco. Accessed January 15, 2021.
http://www.escholarship.org/uc/item/2qg774vw.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Richardson, Christopher Douglas. “Re-Initiation Promoters: Genetic Elements that Modify Cell Cycle Control of Adjacent DNA Replication Origins.” 2014. Web. 15 Jan 2021.
Vancouver:
Richardson CD. Re-Initiation Promoters: Genetic Elements that Modify Cell Cycle Control of Adjacent DNA Replication Origins. [Internet] [Thesis]. University of California – San Francisco; 2014. [cited 2021 Jan 15].
Available from: http://www.escholarship.org/uc/item/2qg774vw.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Richardson CD. Re-Initiation Promoters: Genetic Elements that Modify Cell Cycle Control of Adjacent DNA Replication Origins. [Thesis]. University of California – San Francisco; 2014. Available from: http://www.escholarship.org/uc/item/2qg774vw
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Manitoba
18.
Chuang, Tony Chih-Yuan.
The three-dimensional (3D) organization of telomeres during cellular transformation.
Degree: Physiology, 2010, University of Manitoba
URL: http://hdl.handle.net/1993/4228
► Statement of Problem Telomere dynamics in the three-dimensional (3D) space of the mammalian nucleus plays an important role in the maintenance of genomic stability. However,…
(more)
▼ Statement of Problem
Telomere dynamics in the three-dimensional (3D) space of the mammalian nucleus plays an important role in the maintenance of
genomic stability. However, the telomere distribution in 3D nuclear space of normal and tumor cells was unknown when the study was initiated.
Methods
Telomere fluorescence in situ hybridization (FISH) and 3D molecular imaging, deconvolution, and analysis were used to investigate telomere organization in normal, immortalized and tumor cells from mouse and human cell lines, and primary tissues.
Results
Telomeres are organized in a non-overlapping manner and in a cell-cycle dependant fashion in normal cells. In the late G2 phase of cell cycle, telomeres are assembled into a flattened sphere that is termed the telomeric disk In contrast, the telomeric disk is disrupted in the tumor cells. Moreover, telomeric aggregates (TAs) are found in tumor cells. Conditional c-Myc over-expression induces telomeric aggregation leading to the onset of breakage-bridge-fusion cycles and subsequent chromosomal abnormality.
Conclusions
Telomeres are distributed in a nonrandom and dynamic fashion in the 3D space of a normal cell. Telomeric aggregates are present in cells with
genomic instability such as tumor cells and cells with deregulation of c-Myc. Consequently, TA can be a useful biomarker for research in cancer and other disease processes.
Advisors/Committee Members: Mai, Sabine (Physiology) (supervisor), Kerr, Paul (Otolaryngology Head and Neck Surgery).
Subjects/Keywords: telomere; c-myc; deconvolution; molecular imaging; genomic instability; biomarker
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APA (6th Edition):
Chuang, T. C. (2010). The three-dimensional (3D) organization of telomeres during cellular transformation. (Masters Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/4228
Chicago Manual of Style (16th Edition):
Chuang, Tony Chih-Yuan. “The three-dimensional (3D) organization of telomeres during cellular transformation.” 2010. Masters Thesis, University of Manitoba. Accessed January 15, 2021.
http://hdl.handle.net/1993/4228.
MLA Handbook (7th Edition):
Chuang, Tony Chih-Yuan. “The three-dimensional (3D) organization of telomeres during cellular transformation.” 2010. Web. 15 Jan 2021.
Vancouver:
Chuang TC. The three-dimensional (3D) organization of telomeres during cellular transformation. [Internet] [Masters thesis]. University of Manitoba; 2010. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1993/4228.
Council of Science Editors:
Chuang TC. The three-dimensional (3D) organization of telomeres during cellular transformation. [Masters Thesis]. University of Manitoba; 2010. Available from: http://hdl.handle.net/1993/4228
University of Toronto
19.
Lalonde, Emilie Rose.
Integrative Modelling of Clinical, Genomic, and Microenvironmental Factors for Improved Prediction of Patient Outcome in Localized Prostate Cancer.
Degree: PhD, 2016, University of Toronto
URL: http://hdl.handle.net/1807/75324
► Prostate cancer represents a major global challenge, with 1.1 million new cases in 2012. According to the Public Health Agency of Canada, by 2028 prostate…
(more)
▼ Prostate cancer represents a major global challenge, with 1.1 million new cases in 2012. According to the Public Health Agency of Canada, by 2028 prostate cancer will be the most commonly diagnosed cancer in the country. The vast majority of men will be diagnosed with localized disease and further stratified into low, intermediate and high risk groups based on clinical and pathological features. Despite patient management schemes tailored to these risk groups, significant rates of over- and under-treatment remain.
To improve clinical stratification, molecular features derived from tumour and circulating DNA, RNA and proteins are being evaluated. In prostate cancer, four molecular prognostic signatures (MPS) based on information from derived from RNA and proteins are commercially-available. I hypothesized that molecular features derived from tumour DNA can also be used to develop prognostic MPS. To test this hypothesis, I investigated the ability of copy number alterations (CNAs) to inform patient management in localized prostate cancer. First, I evaluated genes involved in DNA damage sensing as markers of patient response to localized treatment. I found that copy number gains in NBN are predictive for poor outcome in patients treated with radiotherapy but not radical prostatectomy. Next, I evaluated whether combining multiple genes into MPS can improve patient risk stratification. Using an unsupervised approach, I found four molecular subtypes of localized prostate cancer with different patient prognosis. I also identified a synergistic relationship between genomic instability and tumour hypoxia in predicting patient prognosis. Finally, I developed a 100-locus MPS which can identify patients at risk of rapid failure. To ease clinical translation of this MPS, I refined the signature to 31 loci with concordant DNA-RNA changes, and developed a NanoString panel to enable consistent measurement of the MPS in future studies.
These findings demonstrate that CNA-based features are informative of patient outcome and can be additive and even synergistic with micro-environmental and clinico-pathological variables. In the future, incorporating other molecular, micro-environmental, and imaging features can drive further improvements to decrease the burden of over-treatment while minimizing treatment failure rates.
2017-01-08 00:00:00
Advisors/Committee Members: Boutros, Paul C, Bristow, Rob G, Medical Biophysics.
Subjects/Keywords: Biomarker; Gene signature; Genomic instability; Precision medicine; Prognosis; Prostate cancer; 0564
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APA (6th Edition):
Lalonde, E. R. (2016). Integrative Modelling of Clinical, Genomic, and Microenvironmental Factors for Improved Prediction of Patient Outcome in Localized Prostate Cancer. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/75324
Chicago Manual of Style (16th Edition):
Lalonde, Emilie Rose. “Integrative Modelling of Clinical, Genomic, and Microenvironmental Factors for Improved Prediction of Patient Outcome in Localized Prostate Cancer.” 2016. Doctoral Dissertation, University of Toronto. Accessed January 15, 2021.
http://hdl.handle.net/1807/75324.
MLA Handbook (7th Edition):
Lalonde, Emilie Rose. “Integrative Modelling of Clinical, Genomic, and Microenvironmental Factors for Improved Prediction of Patient Outcome in Localized Prostate Cancer.” 2016. Web. 15 Jan 2021.
Vancouver:
Lalonde ER. Integrative Modelling of Clinical, Genomic, and Microenvironmental Factors for Improved Prediction of Patient Outcome in Localized Prostate Cancer. [Internet] [Doctoral dissertation]. University of Toronto; 2016. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1807/75324.
Council of Science Editors:
Lalonde ER. Integrative Modelling of Clinical, Genomic, and Microenvironmental Factors for Improved Prediction of Patient Outcome in Localized Prostate Cancer. [Doctoral Dissertation]. University of Toronto; 2016. Available from: http://hdl.handle.net/1807/75324
Duke University
20.
Dulmage, Keely.
Large-scale Effectors of Gene Expression and New Models of Cell Division in the Haloarchaea.
Degree: 2015, Duke University
URL: http://hdl.handle.net/10161/11341
► Like most Archaea, the hypersaline-adapted organism Halobacterium salinarum exhibits characteristics from all three domains of life, including a eukaryotic histone protein, a universal propensity…
(more)
▼ Like most Archaea, the hypersaline-adapted organism Halobacterium salinarum exhibits characteristics from all three domains of life, including a eukaryotic histone protein, a universal propensity to genetic rearrangements, and homologs of bacterial cell division proteins. Here we investigate the ancestral function of histone protein in the Archaea. Transcriptomics, proteomics, and phenotypic assays of histone mutants determine that histone regulates gene expression and cell shape but not genome compaction in H. salinarum. We further explore the regulation of gene expression on a genome-wide scale through the study of
genomic instability.
Genomic deletions and duplications are detected through the meta-analysis of 1154 previously published gene expression arrays and 48 chromatin immunoprecipitation arrays. We discover that a 90 kb duplication event in the megaplasmid pNRC100 directly leads to increased gene expression, and find evidence that the chromosome is far more unstable than previously assumed. These events are all linked with the presence of mobile insertion elements. Finally, in response to questions generated by these experiments, we develop a novel time-lapse protocol for H. salinarum and ask basic questions about single cell dynamics during division. Fluorescent labeling of homologs to bacterial cell division proteins confirms their involvement in cell division but localization dynamics contradict the basic bacterial model. The discovery of unusual facets of morphology during cell division is consistent with these novel protein dynamics and opens up new avenues of inquiry into archaeal cell division.
Advisors/Committee Members: Schmid, Amy (advisor).
Subjects/Keywords: Microbiology;
Genetics;
Molecular biology;
Archaea;
Cell division;
Genomic instability;
Halophiles;
Histone
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APA (6th Edition):
Dulmage, K. (2015). Large-scale Effectors of Gene Expression and New Models of Cell Division in the Haloarchaea.
(Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/11341
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Dulmage, Keely. “Large-scale Effectors of Gene Expression and New Models of Cell Division in the Haloarchaea.
” 2015. Thesis, Duke University. Accessed January 15, 2021.
http://hdl.handle.net/10161/11341.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Dulmage, Keely. “Large-scale Effectors of Gene Expression and New Models of Cell Division in the Haloarchaea.
” 2015. Web. 15 Jan 2021.
Vancouver:
Dulmage K. Large-scale Effectors of Gene Expression and New Models of Cell Division in the Haloarchaea.
[Internet] [Thesis]. Duke University; 2015. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/10161/11341.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Dulmage K. Large-scale Effectors of Gene Expression and New Models of Cell Division in the Haloarchaea.
[Thesis]. Duke University; 2015. Available from: http://hdl.handle.net/10161/11341
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Edinburgh
21.
Boteva, Lora.
Investigating transcription, replication and chromatin structure in determining common fragile site instability.
Degree: PhD, 2017, University of Edinburgh
URL: http://hdl.handle.net/1842/28803
► Common fragile sites are a set of genomic locations with a propensity to form lesions, breaks and gaps on mitotic chromosomes upon induction of replication…
(more)
▼ Common fragile sites are a set of genomic locations with a propensity to form lesions, breaks and gaps on mitotic chromosomes upon induction of replication stress. While the exact reasons for their fragility are unknown, CFS display instability in a cell-type specific manner, suggesting a substantial contribution from an epigenetic component. CFSs also overlap with sites of increased breakage and deletions in tumour cells, as well as evolutionary breakpoints, implying that their features shape genome stability in vivo. Previously, factors such as delays in replication timing, low origin density and transcription of long genes have been implicated in instability at CFS locations but comprehensive molecular studies are lacking. Chromatin structure, an important factor that fits the profile of cell-type specific contributor, has also not been investigated yet. Throughout their efforts to determine the factors that lead to the appearance of CFS lesions, investigators have focused on a single component at a time, potentially missing out complex interactions between cellular processes that could underlie fragility. Additional difficulties come from the cell-type specificity of CFS breakage: it indicates that only cell type-matched data would be informative, limiting the scope for studies using publicly available data. To perform a comprehensive study defining the role of different factors in determining CFS fragility, I explored replication timing, transcriptional landscapes and chromatin environment across a number of CFSs in two cell types exhibiting differential CFS breakage. Initially, I characterised the patterns of CFS fragility in the two cell types on both the cytogenetic and the molecular level. I then used a FISH-based technique to investigate the process of mitotic compaction at active CFS sites and found that the cytogenetically fragile core of these sites sits within larger regions which display a tendency to mis-fold in mitosis. The aberrant compaction of these regions could be observed on cytogenetically normal metaphase chromosomes, suggesting that finer scale abnormalities in chromosome structure underlie the cytogenetically visible breaks at fragile sites. I also investigated the links between transcription of long genes and CFS fragility using two approaches: I quantified levels of expression across all fragile sites using RNA-seq and modified transcription at a single active CFS using the CRISPR genome engineering methodology. My results indicate a complex interplay between transcription and CFS fragility: no simple linear correlation can be observed, but an increase of transcriptional levels at the active CFS led to a corresponding increase in fragility. To investigate the influence of the cell type specific replication programme and replication stress on CFS instability, I mapped replication timing genome-wide in unperturbed cells and under conditions of replication stress in both cell types. I found that replication stress induces bi-directional changes in replication timing throughout the genome as…
Subjects/Keywords: common fragile sites; CFS fragility; mitotic compaction; cytogenetic lesions; genomic instability
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APA ·
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APA (6th Edition):
Boteva, L. (2017). Investigating transcription, replication and chromatin structure in determining common fragile site instability. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/28803
Chicago Manual of Style (16th Edition):
Boteva, Lora. “Investigating transcription, replication and chromatin structure in determining common fragile site instability.” 2017. Doctoral Dissertation, University of Edinburgh. Accessed January 15, 2021.
http://hdl.handle.net/1842/28803.
MLA Handbook (7th Edition):
Boteva, Lora. “Investigating transcription, replication and chromatin structure in determining common fragile site instability.” 2017. Web. 15 Jan 2021.
Vancouver:
Boteva L. Investigating transcription, replication and chromatin structure in determining common fragile site instability. [Internet] [Doctoral dissertation]. University of Edinburgh; 2017. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1842/28803.
Council of Science Editors:
Boteva L. Investigating transcription, replication and chromatin structure in determining common fragile site instability. [Doctoral Dissertation]. University of Edinburgh; 2017. Available from: http://hdl.handle.net/1842/28803
University of Lethbridge
22.
Sidler, Corinne.
A Role of Epigenetics in Aging and the Age-Dependent Response to Ionizing Radiation
.
Degree: 2014, University of Lethbridge
URL: http://hdl.handle.net/10133/3508
► Aging is associated with the functional decline of organs, and results in age-dependent differences in stress-sensitivity. Younger animals are more sensitive to mutagenic insults than…
(more)
▼ Aging is associated with the functional decline of organs, and results in age-dependent differences in stress-sensitivity. Younger animals are more sensitive to mutagenic insults than adults, whereas in plants, the transition to reproductive growth is the most stress-sensitive.
Here, we show a role of reduced H3K9 trimethylation and corresponding genomic instability in the aging rat thymus and in senescence of human fibroblasts. A similar reduction of SUV39H1 expression was observed in response to ionizing radiation (IR), which correlated with the induction of senescence.
In plants exposed to IR during the transition to reproductive growth, histone methyltransferases were up-regulated, which correlated with reduced transcription of transposable elements.
This difference in response may be reflected in the differences in life cycles. Whereas plants rely on the survival and genome integrity of meristematic cells for their reproductive success, in mammals, limiting the cell division in cells that have incurred damage may be crucial.
Subjects/Keywords: aging;
genomic instability;
histone methyltransferases;
human fibroblasts;
ionizing radiation;
life cyces
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APA (6th Edition):
Sidler, C. (2014). A Role of Epigenetics in Aging and the Age-Dependent Response to Ionizing Radiation
. (Thesis). University of Lethbridge. Retrieved from http://hdl.handle.net/10133/3508
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Sidler, Corinne. “A Role of Epigenetics in Aging and the Age-Dependent Response to Ionizing Radiation
.” 2014. Thesis, University of Lethbridge. Accessed January 15, 2021.
http://hdl.handle.net/10133/3508.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sidler, Corinne. “A Role of Epigenetics in Aging and the Age-Dependent Response to Ionizing Radiation
.” 2014. Web. 15 Jan 2021.
Vancouver:
Sidler C. A Role of Epigenetics in Aging and the Age-Dependent Response to Ionizing Radiation
. [Internet] [Thesis]. University of Lethbridge; 2014. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/10133/3508.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Sidler C. A Role of Epigenetics in Aging and the Age-Dependent Response to Ionizing Radiation
. [Thesis]. University of Lethbridge; 2014. Available from: http://hdl.handle.net/10133/3508
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Queens University
23.
Jarvis, Morgan L.
Development of a novel screen protocol for the identification of genes causing replication associated genomic instability in Schizosaccharomyces pombe
.
Degree: Pathology and Molecular Medicine, 2008, Queens University
URL: http://hdl.handle.net/1974/1227
► Replication fork stalling is a source of potentially tumourigenic genomic instability. The RecQ family helicase, Rqh1, is critical for the prevention of replication fork collapse…
(more)
▼ Replication fork stalling is a source of potentially tumourigenic genomic instability. The RecQ family helicase, Rqh1, is critical for the prevention of replication fork collapse and the formation of potentially deleterious recombination intermediates following fork stalling. Previous work in our lab with Schizosaccharomyces pombe (fission yeast) has shown that rqh10/rqh10 diploids are inherently unstable and show rapid reversion to the haploid state. The current work exploits this characteristic of fission yeast rqh10 mutants in a screen for genes that normally promote replication associated genomic instability. The rqh10rad30 mutant strains employed in this work incorporate the checkpoint deficiency caused by a lack of Rad3, so as to exacerbate the genomically unstable nature of this model. The current work describes the lithium acetate transformation based random mutagenesis by non-homologous integration of the ura4+ selectable marker into the rqh10rad30 fission yeast strains. This random mutagenesis generated extensive (24,500 – 50,000) mutant libraries. The quality of the libraries was assessed by can1 mutant assay, confirming an adequately extensive mutagenesis for the proposed screen. The process to be employed in the screen would involve the crossing of the mutant libraries, with the hope of generating diploids that will have two mutant copies of the same gene. Some of these diploids would appear unusually stable, showing a normal sporulation phenotype. This would indicate the mutation of a gene that normally promotes genomic instability following replication fork stalling. The practicality of the proposed screen of a vast number of diploids was assessed and described in detail in the current work. A technique involving inverse PCR (IPCR) adopted from previous work to identify mutants of interest, was also investigated. The investigation of this technique, and the work of others, suggests that transformation using such selectable marker fragments results in most apparent transformants containing extrachromosomal ura4+ fragments. These fragments are thought to provide the predominant template for IPCR, rendering the process unsuccessful at identifying the mutation in the current screen. However, with the mutant libraries generated, and the screen procedure detailed, the stage is set to conduct the screen once a more appropriate mutation location technique is identified.
Subjects/Keywords: Genomic instability
;
DNA replication
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APA (6th Edition):
Jarvis, M. L. (2008). Development of a novel screen protocol for the identification of genes causing replication associated genomic instability in Schizosaccharomyces pombe
. (Thesis). Queens University. Retrieved from http://hdl.handle.net/1974/1227
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Jarvis, Morgan L. “Development of a novel screen protocol for the identification of genes causing replication associated genomic instability in Schizosaccharomyces pombe
.” 2008. Thesis, Queens University. Accessed January 15, 2021.
http://hdl.handle.net/1974/1227.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Jarvis, Morgan L. “Development of a novel screen protocol for the identification of genes causing replication associated genomic instability in Schizosaccharomyces pombe
.” 2008. Web. 15 Jan 2021.
Vancouver:
Jarvis ML. Development of a novel screen protocol for the identification of genes causing replication associated genomic instability in Schizosaccharomyces pombe
. [Internet] [Thesis]. Queens University; 2008. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1974/1227.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Jarvis ML. Development of a novel screen protocol for the identification of genes causing replication associated genomic instability in Schizosaccharomyces pombe
. [Thesis]. Queens University; 2008. Available from: http://hdl.handle.net/1974/1227
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Louisiana State University
24.
Han, Kyudong.
Retrotransposon mediated genomic fluidity in the human and chimpanzee lineages.
Degree: PhD, 2006, Louisiana State University
URL: etd-08302006-100849
;
https://digitalcommons.lsu.edu/gradschool_dissertations/807
► LINE-1s (Long interspersed elements or L1s) and Alus are highly successful non-long terminal repeat retrotransposons with copy numbers of ~520,000 and >1 million within the…
(more)
▼ LINE-1s (Long interspersed elements or L1s) and Alus are highly successful non-long terminal repeat retrotransposons with copy numbers of ~520,000 and >1 million within the human genome, respectively. They are associated with human genetic variation and genomic rearrangement. Although they are abundant throughout primate genomes, their propagation strategy remains poorly understood. The recently released human and chimpanzee draft genome sequences provide the opportunity to compare the human genome with the chimpanzee genome. Thus, we were able to assess how these elements expanded in primate genomes and how they create genomic instability during their integration into the host genome as well as subsequent post-insertion recombination between elements. To understand the expansion of Alu elements, we first analyzed the evolutionary history of the AluYb lineage which is one of most active Alu lineages in the human genome. We suggest that the evolutionary success of Alu elements is driven at least in part by “stealth driver” elements that maintain low retrotransposition activity over extended periods of time and occasionally produce short-lived hyperactive copies responsible for the formation and remarkable expansion of Alu elements within the genome. Second, we conducted a detailed characterization of chimpanzee-specific L1 subfamily diversity. Our results showed that L1 elements have experienced different evolutionary fates in humans and chimpanzees lineages. These differential evolutionary paths may be the result of random variation or the product of competition between L1 subfamily lineages. Third, we report 50 deletion events in human and chimpanzee genomes directly linked to the insertion of L1 elements, resulting in the loss of ~18 kb of human genomic sequence and ~15 kb of chimpanzee genomic sequence. This study provides the basis for developing models of the mechanisms for small and large L1 insertion-mediated deletions. Fourth, we analyzed the magnitude of Alu recombination-mediated deletions in the human lineage subsequent to the human-chimpanzee divergence. We identified 492 human-specific deletions (for a total of ~400 kb of sequence) attributable to this process. The majority of the deletions coincide with known or predicted genes, which implicates this process in creating a substantial portion of the genomic differences between humans and chimpanzees.
Subjects/Keywords: genomic deletion; comparative genomics; genomic instability; primate evolution; retrotransposons
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APA (6th Edition):
Han, K. (2006). Retrotransposon mediated genomic fluidity in the human and chimpanzee lineages. (Doctoral Dissertation). Louisiana State University. Retrieved from etd-08302006-100849 ; https://digitalcommons.lsu.edu/gradschool_dissertations/807
Chicago Manual of Style (16th Edition):
Han, Kyudong. “Retrotransposon mediated genomic fluidity in the human and chimpanzee lineages.” 2006. Doctoral Dissertation, Louisiana State University. Accessed January 15, 2021.
etd-08302006-100849 ; https://digitalcommons.lsu.edu/gradschool_dissertations/807.
MLA Handbook (7th Edition):
Han, Kyudong. “Retrotransposon mediated genomic fluidity in the human and chimpanzee lineages.” 2006. Web. 15 Jan 2021.
Vancouver:
Han K. Retrotransposon mediated genomic fluidity in the human and chimpanzee lineages. [Internet] [Doctoral dissertation]. Louisiana State University; 2006. [cited 2021 Jan 15].
Available from: etd-08302006-100849 ; https://digitalcommons.lsu.edu/gradschool_dissertations/807.
Council of Science Editors:
Han K. Retrotransposon mediated genomic fluidity in the human and chimpanzee lineages. [Doctoral Dissertation]. Louisiana State University; 2006. Available from: etd-08302006-100849 ; https://digitalcommons.lsu.edu/gradschool_dissertations/807
Texas Medical Center
25.
Pal, Sangita.
UNDERSTANDING THE MECHANISM OF GENOMIC INSTABILITY DURING REPLICATIVE AGING IN BUDDING YEAST.
Degree: PhD, 2017, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/770
► Aging brings a gradual decline in molecular fidelity and biological functionality, resulting in age related phenotypes and diseases. Despite continued efforts to uncover the…
(more)
▼ Aging brings a gradual decline in molecular fidelity and biological functionality, resulting in age related phenotypes and diseases. Despite continued efforts to uncover the conserved aging pathways among eukaryotes, exact molecular causes of aging are still poorly understood. One of the most important hallmarks of aging is increased
genomic instability. However, there remains much ambiguity as to the cause. I am studying the replicative life span (RLS) of the genetically tractable model organism Saccharomyces cerevisiae, or budding yeast using the innovative “mother enrichment program” as the method to isolate unparalleled numbers of aged yeast cells to investigate the molecular changes associated with aging. My goal is to determine the possible causes of loss of
genomic integrity during replicative aging in budding yeast to gain potential insight into this vastly complex process.
In my work presented here, I uncovered a global loss of cohesion in mitotically aged yeast cells and this most likely serves as the cause of increased rDNA
instability and/or ERC accumulation as observed during aging. These events, in turn, influence the global
genomic integrity in replicatively aged cells. Furthermore, I discovered a profound defect in double strand break (DSB) repair with aging due to limiting levels of key components of the homologous recombination machinery. This DSB repair defect in old cells limited the replicative lifespan, because restoration of DSB repair by overexpressing key HR proteins ameliorated age-associated changes, to extend lifespan. We propose that the limiting levels of repair factors and cohesin proteins impair the ability of the aged cells to counteract the increased burden of
genomic damage accumulation coupled with chromosomal rearrangements and potentially chromosome loss, eventually to cross a threshold of
genomic damage that is sensed by the cell to cause cessation of cell division marking the end of the replicative lifespan.
Advisors/Committee Members: Jessica K. Tyler, Ph.D., Pierre D. McCrea, Ph.D., Xiaobing Shi, Ph.D..
Subjects/Keywords: Replicative aging; Genomic instability; rDNA instability; Double-strand break repair; Cohesin; Biochemistry; Cell Biology; Molecular Biology; Molecular Genetics
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APA (6th Edition):
Pal, S. (2017). UNDERSTANDING THE MECHANISM OF GENOMIC INSTABILITY DURING REPLICATIVE AGING IN BUDDING YEAST. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/770
Chicago Manual of Style (16th Edition):
Pal, Sangita. “UNDERSTANDING THE MECHANISM OF GENOMIC INSTABILITY DURING REPLICATIVE AGING IN BUDDING YEAST.” 2017. Doctoral Dissertation, Texas Medical Center. Accessed January 15, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/770.
MLA Handbook (7th Edition):
Pal, Sangita. “UNDERSTANDING THE MECHANISM OF GENOMIC INSTABILITY DURING REPLICATIVE AGING IN BUDDING YEAST.” 2017. Web. 15 Jan 2021.
Vancouver:
Pal S. UNDERSTANDING THE MECHANISM OF GENOMIC INSTABILITY DURING REPLICATIVE AGING IN BUDDING YEAST. [Internet] [Doctoral dissertation]. Texas Medical Center; 2017. [cited 2021 Jan 15].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/770.
Council of Science Editors:
Pal S. UNDERSTANDING THE MECHANISM OF GENOMIC INSTABILITY DURING REPLICATIVE AGING IN BUDDING YEAST. [Doctoral Dissertation]. Texas Medical Center; 2017. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/770
Mississippi State University
26.
Esteban-Perez, Clara Ines.
GENOMIC INSTABILITY MAY BE A SIGNAL OF HUMAN EMBRYONIC STEM CELL DIFFERENTIATION.
Degree: PhD, Biological Sciences, 2011, Mississippi State University
URL: http://sun.library.msstate.edu/ETD-db/theses/available/etd-04082011-115340/
;
► Embryonic stem (ES) cells have the ability to maintain pluripotency and self-renewal during <i>in vitro</i> maintenance, which is a key to their clinical applications.…
(more)
▼ Embryonic stem (ES) cells have the ability to maintain
pluripotency and self-renewal during <i>in
vitro</i> maintenance, which is a key to their clinical applications. ES cells
are a model in developmental biology studies due to their potential to
differentiate <i>in vitro. </i>Understanding critical pathways of
pluripotency, self-renewal, and differentiation during early embryonic development
is important for the evaluation of the therapeutic potential of ES cells
because of their ability for tumor transformation due to genetic and epigenetic
instability acquired during <i>in vitro</i>
culture maintenance. Single tandem repeats are sequences of DNA that have been
implicated in the deregulation of gene expression in different human conditions.
Understanding the origin of repetitive sequence
instability and functions in
the genome allow characterization of early
genomic instability signals in ES cell
pluripotency, differentiation, and tumor transformation pathways. The
hypothesis of this study was that genetic stability, in repetitive sequences,
located near embryonic developmental genes is responsible for pluripotency, self-renewal,
differentiation, and chromatin assembly and could be a signal for adaptation, differentiation,
or transformation of ES cells <i>in vitro.</i>
Our result showed
instability in specific repetitive sequences which increased
during ES cell passages and embryoid body differentiation <i>in vitro.</i> ES cells displayed significant mean frequencies of
genomic
instability in repetitive regions that lead to ES cells pluripotency,
self-renewal maintenance, or cell lineage specialization. The present study
reports potentially biomarkers for identifying accumulation of
genomic
instability in specific genes that may contributes to adaptation of ES cells
and could be the switch that initiates early ES cell lineage commitment <i>in vitro</i>. Determining genetic and
epigenetic modifications, including single tandem repeat
instability, gene
expression changes, and chromatin modifications, is essential for elucidating possible
molecular mechanisms of
genomic instability and determining novel molecular
characterization for diagnostic purposes to ensure ES cell stability and
integrity that could potentially lead to use of ES cell derivatives that could
then be a safe source needed for regenerative medicine applications
Advisors/Committee Members: Peter L. Ryan (committee member), Karen S. Coats (committee member), Janet R. Donaldson (committee member), Nancy A. Reichert (chair), Dwayne A. Wise (chair).
Subjects/Keywords: genomic instability; cell lineage commitment; cell differentiation; pluripotency; Embryonic stem cell; repetitive sequences; tumor transformation.
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APA (6th Edition):
Esteban-Perez, C. I. (2011). GENOMIC INSTABILITY MAY BE A SIGNAL OF HUMAN EMBRYONIC STEM CELL DIFFERENTIATION. (Doctoral Dissertation). Mississippi State University. Retrieved from http://sun.library.msstate.edu/ETD-db/theses/available/etd-04082011-115340/ ;
Chicago Manual of Style (16th Edition):
Esteban-Perez, Clara Ines. “GENOMIC INSTABILITY MAY BE A SIGNAL OF HUMAN EMBRYONIC STEM CELL DIFFERENTIATION.” 2011. Doctoral Dissertation, Mississippi State University. Accessed January 15, 2021.
http://sun.library.msstate.edu/ETD-db/theses/available/etd-04082011-115340/ ;.
MLA Handbook (7th Edition):
Esteban-Perez, Clara Ines. “GENOMIC INSTABILITY MAY BE A SIGNAL OF HUMAN EMBRYONIC STEM CELL DIFFERENTIATION.” 2011. Web. 15 Jan 2021.
Vancouver:
Esteban-Perez CI. GENOMIC INSTABILITY MAY BE A SIGNAL OF HUMAN EMBRYONIC STEM CELL DIFFERENTIATION. [Internet] [Doctoral dissertation]. Mississippi State University; 2011. [cited 2021 Jan 15].
Available from: http://sun.library.msstate.edu/ETD-db/theses/available/etd-04082011-115340/ ;.
Council of Science Editors:
Esteban-Perez CI. GENOMIC INSTABILITY MAY BE A SIGNAL OF HUMAN EMBRYONIC STEM CELL DIFFERENTIATION. [Doctoral Dissertation]. Mississippi State University; 2011. Available from: http://sun.library.msstate.edu/ETD-db/theses/available/etd-04082011-115340/ ;
27.
Bodnar-Wachtel, Mélanie.
Étude du rôle de NLRP3 dans la tumorigenèse pulmonaire : Role of NLRP3 in lung cancer development.
Degree: Docteur es, Immunologie, 2015, Université Claude Bernard – Lyon I
URL: http://www.theses.fr/2015LYO10184
► Mon travail de thèse s'intéresse au rôle du récepteur à l'immunité innée NLRP3, composant essentiel de l'inflammasome, dans le développement tumoral pulmonaire. Nos résultats révèlent…
(more)
▼ Mon travail de thèse s'intéresse au rôle du récepteur à l'immunité innée NLRP3, composant essentiel de l'inflammasome, dans le développement tumoral pulmonaire. Nos résultats révèlent que les cellules épithéliales pulmonaires immortalisées expriment un inflammasome NLRP3 fonctionnel. De façon inattendue, nous montrons que l'expression du récepteur NLRP3 est fortement diminuée, voire perdue des lignées tumorales de CBNPC et dans des tumeurs de patients, comparé au tissu sain adjacent. Nous montrons que NLRP3, de façon totalement indépendante de l'inflammasome, est impliquée dans la régulation transcriptionnelle de H2AFX, le gène codant pour le variant d'histone H2AX, élément clé de la signalisation des dommages à l'ADN. L'absence de NLRP3 dans les cellules HBEC altère l'amplification et la transmission du signal en réponse à des cassures double brin, résultant in fine à moins de réparation. Ce défaut de réparation des cassures se traduit par une instabilité génomique, qui est en effet plus forte dans les adénocarcinomes pulmonaires exprimant de faible niveau de NLRP3. Mon travail de thèse identifie donc le récepteur NLRP3 comme un facteur clé de la réponse aux dommages à l'ADN et du maintien de l'intégrité génomique en promouvant la transcription de H2AFX dans les cellules épithéliales pulmonaires. Ce nouveau rôle de NLRP3, associé à sa perte dans les tumeurs de CBPNC en font un potentiel suppresseur de tumeur
During my PhD, I have been interested in the role of the innate immune receptor NLRP3, a key component of the inflammasome, in lung cancer development. Our results show the presence of a functional NLRP3 inflammasome in normal human bronchial epithelial cells (HBEC). Surprisingly, NLRP3 expression is strongly down-regulated in a large panel of NSCLC cell lines and patient tumors compared to healthy tissue. Moreover, we unravel that NLRP3 contributes to the transcription of H2AFX, the coding gene for the histone variant H2AX, in an inflammasome independent-manner. The deletion of NLRP3 in HBEC impairs double strand break signal amplification and transduction, resulting in a decrease in DNA repair. This repair defect leads to genomic instability, which is increased in lung adenocarcinomas expressing low levels of NLRP3. My PhD work identifies NLRP3 as a key factor of the DNA damage response and genomic integrity maintenance by regulating the transcription of H2AFX. This new role for NLRP3, together with its loss in NSCLC, makes it as a potential tumor suppressor
Advisors/Committee Members: Petrilli, Virginie (thesis director).
Subjects/Keywords: NLRP3; H2AFX; CBNPC; Réparation; Instabilité génomique; NLRP3; H2AFX; NSCLC; DNA repair; Genomic instability; 571.96
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APA (6th Edition):
Bodnar-Wachtel, M. (2015). Étude du rôle de NLRP3 dans la tumorigenèse pulmonaire : Role of NLRP3 in lung cancer development. (Doctoral Dissertation). Université Claude Bernard – Lyon I. Retrieved from http://www.theses.fr/2015LYO10184
Chicago Manual of Style (16th Edition):
Bodnar-Wachtel, Mélanie. “Étude du rôle de NLRP3 dans la tumorigenèse pulmonaire : Role of NLRP3 in lung cancer development.” 2015. Doctoral Dissertation, Université Claude Bernard – Lyon I. Accessed January 15, 2021.
http://www.theses.fr/2015LYO10184.
MLA Handbook (7th Edition):
Bodnar-Wachtel, Mélanie. “Étude du rôle de NLRP3 dans la tumorigenèse pulmonaire : Role of NLRP3 in lung cancer development.” 2015. Web. 15 Jan 2021.
Vancouver:
Bodnar-Wachtel M. Étude du rôle de NLRP3 dans la tumorigenèse pulmonaire : Role of NLRP3 in lung cancer development. [Internet] [Doctoral dissertation]. Université Claude Bernard – Lyon I; 2015. [cited 2021 Jan 15].
Available from: http://www.theses.fr/2015LYO10184.
Council of Science Editors:
Bodnar-Wachtel M. Étude du rôle de NLRP3 dans la tumorigenèse pulmonaire : Role of NLRP3 in lung cancer development. [Doctoral Dissertation]. Université Claude Bernard – Lyon I; 2015. Available from: http://www.theses.fr/2015LYO10184
Cornell University
28.
Balmus, Gabriel.
Roles For The Dna Damage Checkpoint Gene Hus1 In Responding To Endogenous And Exogenous Stresses In Vivo.
Degree: PhD, Physiology, 2013, Cornell University
URL: http://hdl.handle.net/1813/33855
► The DNA damage response (DDR) represents the primary line of defense against exogenous and endogenous genotoxic agents that threaten the stability of our genomes. The…
(more)
▼ The DNA damage response (DDR) represents the primary line of defense against exogenous and endogenous genotoxic agents that threaten the stability of our genomes. The ATM and ATR pathways are central to the response to DNA-damage and their understanding can bring important information in the fight against inborn disease and cancer. While the roles for the ATM pathway in DDR are well understood, the lack of a model organism for the ATR pathway has impeded its understanding. Here I show how we use Hus1, a component of the RAD9-RAD1-HUS1 heterotrimeric clamp and a vital member of the ATR pathway, to deregulate the ATR pathway and dissect its importance in development and disease. This was done by engineering in mice a Hus1 allelic series by combining the wild-type (Hus1+) with a hypomorphic (Hus1neo) or null (Hus1[DELTA]1) alleles. As opposed to the germline constitutive deletion that leads to embryonic lethality, Hus1 hypomorphic mice are born at expected frequencies and show no overt phenotype but have increased levels of
genomic instability. Thus they have enough Hus1 to deal with physiologic stress and could be used for our research. iii To investigate the in vivo physiologic relationship between the ATM and ATR pathways I crossed the Hus1 allelic series on an Atm null background and showed that the interaction between the two pathways is critical for normal development. When the two pathways are deregulated simultaneously a synthetic lethal interaction is created. While part of the Hus1/Atm double mutant mice die during development due an apparent incapability to deal with replication stress, the survivors suffer from developmental defects including dwarfism and skeletal defects. To further understand the interplay between these two pathways in response to genotoxins Hus1 single mutant and Hus1/Atm double mutant mice were subjected to specific genotoxin treatments. This analysis showed that in adult tissues there is a clear separation of function between the ATM and ATR pathways, with ATM being the main responde r to DNA breaks while the ATR pathway responds mainly to replication stress such as that caused by mitomycin C. In summary this thesis brings important new information about the relationship between the two main DDR response pathways leaded by ATM and ATR and substantiates their joint role in development and disease. Moreover we now have a better understanding of how these interactions can be used for creating better therapies. iv
Advisors/Committee Members: Weiss, Robert S. (chair), Nikitin, Alexander (committee member), Schimenti, John C. (committee member), Alani, Eric (committee member).
Subjects/Keywords: DNA damage; ATM; ATR; HUS1; cell cycle checkpoints; cancer; development; genomic instability
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APA (6th Edition):
Balmus, G. (2013). Roles For The Dna Damage Checkpoint Gene Hus1 In Responding To Endogenous And Exogenous Stresses In Vivo. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/33855
Chicago Manual of Style (16th Edition):
Balmus, Gabriel. “Roles For The Dna Damage Checkpoint Gene Hus1 In Responding To Endogenous And Exogenous Stresses In Vivo.” 2013. Doctoral Dissertation, Cornell University. Accessed January 15, 2021.
http://hdl.handle.net/1813/33855.
MLA Handbook (7th Edition):
Balmus, Gabriel. “Roles For The Dna Damage Checkpoint Gene Hus1 In Responding To Endogenous And Exogenous Stresses In Vivo.” 2013. Web. 15 Jan 2021.
Vancouver:
Balmus G. Roles For The Dna Damage Checkpoint Gene Hus1 In Responding To Endogenous And Exogenous Stresses In Vivo. [Internet] [Doctoral dissertation]. Cornell University; 2013. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1813/33855.
Council of Science Editors:
Balmus G. Roles For The Dna Damage Checkpoint Gene Hus1 In Responding To Endogenous And Exogenous Stresses In Vivo. [Doctoral Dissertation]. Cornell University; 2013. Available from: http://hdl.handle.net/1813/33855
Vanderbilt University
29.
Tidball, Andrew Martin.
A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling.
Degree: PhD, Neuroscience, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/14230
► The essential micronutrient manganese is enriched in brain, especially the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels,…
(more)
▼ The essential micronutrient manganese is enriched in brain, especially the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels, as previous data suggested manganese alterations occur in Huntington’s disease (HD). We found that p53 phosphorylation is highly responsive to manganese levels in human and mouse striatal-like neuroprogenitors. The Ataxia Telangiectasia Mutated (ATM) kinase is responsible for this manganese-dependent phosphorylation of p53. Activation of ATM-p53 by manganese was severely blunted by pathogenic alleles of Huntingtin. HD neuroprogenitors exhibited a highly manganese selective deficit in ATM kinase activation, since DNA damage and oxidative injury, canonical activators of ATM, did not show similar deficits. Manganese was previously shown to activate ATM kinase in cell-free assays. We found that human HD neuroprogenitors have reduced intracellular manganese with neurologically relevant manganese exposures. Pharmacological manipulation to equalize manganese between HD and control neuroprogenitors rescued the ATM-p53 signaling deficit. The compound that normalized these levels was the small molecule, KB-R7943, a known inhibitor sodium/calcium exchanger (NCX) inhibitor. However, the mechanism by which KB-R7943 corrects manganese accumulation does not seem to be via direct inhibition of the NCX transporters. We also demonstrated a severe deficit in NCX1 expression in HD cells that may also play a key role in the HD manganese deficiency.
Huntington’s disease cells also show increased
genomic instability and DNA damage signaling under basal conditions. Manganese is known to be an important cofactor for several enzymes involved in DNA repair and replication, and we found that the manganese deficiency was most severe in the nucleus compared with other compartments. Manganese supplementation reduced the elevated DNA damage signaling to those found in non-HD cells suggesting that manganese deficiency underlies this phenotype
In short, the ATM-p53 signaling pathway is a manganese responsive signaling pathway. Manganese is an important cofactor with diminished accumulation in HD cell models. These reduced levels may be the reason for observed increases in DNA damage and
genomic instability. Further experimentation is needed to elucidate the mechanism of manganese accumulation deficiency mechanism in HD and the KB-R7943 rescue.
Advisors/Committee Members: Christopher V. Wright (committee member), Michael Aschner (committee member), Aaron B. Bowman (committee member), Kevin C. Ess (Committee Chair).
Subjects/Keywords: manganese; induced-pluripotent stem cells; ATM; p53; cell signaling; cytotoxicity; genomic instability; Huntingtons disease
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APA (6th Edition):
Tidball, A. M. (2014). A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14230
Chicago Manual of Style (16th Edition):
Tidball, Andrew Martin. “A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 15, 2021.
http://hdl.handle.net/1803/14230.
MLA Handbook (7th Edition):
Tidball, Andrew Martin. “A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling.” 2014. Web. 15 Jan 2021.
Vancouver:
Tidball AM. A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1803/14230.
Council of Science Editors:
Tidball AM. A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14230
Queen Mary, University of London
30.
Patani, Hemalvi.
Investigating cancer-like DNA methylation patterns and genome stability upon reprogramming to naïve human pluripotency.
Degree: PhD, 2019, Queen Mary, University of London
URL: http://qmro.qmul.ac.uk/xmlui/handle/123456789/60605
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.791864
► Aberrant DNA hypermethylation of promoter CpG islands in the context of a hypomethylated genome is a hallmark of cancer. DNA hypomethylation is typically associated with…
(more)
▼ Aberrant DNA hypermethylation of promoter CpG islands in the context of a hypomethylated genome is a hallmark of cancer. DNA hypomethylation is typically associated with genomic instability while CpG island hypermethylation is often linked to gene repression. The mechanisms underlying these changes and the role they play in cancer initiation and progression remain elusive as they are challenging to study once cancers have progressed, and no human experimental models exist to mechanistically investigate this phenomenon. We observed that upon reprogramming of primed human embryonic stem cells to the naïve state, the acquisition of a globally hypomethylated genome is accompanied by hypermethylation of bivalent promoter CpG islands, thus resembling DNA methylation patterns characteristic of the human cancer methylome. We dissected the kinetics of these DNA methylation changes at high temporal resolution. We found that a subset of bivalent genes which are enriched in developmental pathways become hypermethylated, and showed that this is mirrored across multiple cancers, suggesting common underlying mechanisms of DNA hypermethylation. To gain insight into the mechanism of hypermethylation, we investigated the dynamic expression of DNA methylation regulators upon reprogramming. We identified the de novo DNA methyltransferase DNMT3A as the enzyme primarily responsible for DNA hypermethylation, and characterised the consequences of its absence on the naïve pluripotent state. Additionally, we demonstrated a role of transcription factors and the pluripotency network in coordinating de novo methylation. In parallel, we explored the impact of reprogramming on the genomic stability of naïve hESCs and investigated a potential relationship between reprogramming and DNA mutations. We observed evidence of chromosomal instability upon reprogramming, though the mutation frequency appears to remain unchanged. The similarities between DNA methylation patterns acquired during reprogramming to naïve pluripotency and oncogenic transformation, as well as indications of genomic instability upon reprogramming suggest a wider utility for this reprogramming system in understanding cancer formation.
Subjects/Keywords: Medicine and Dentistry; DNA hypermethylation; genomic instability; gene repression; cancer initiation; oncogenic transformation
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Patani, H. (2019). Investigating cancer-like DNA methylation patterns and genome stability upon reprogramming to naïve human pluripotency. (Doctoral Dissertation). Queen Mary, University of London. Retrieved from http://qmro.qmul.ac.uk/xmlui/handle/123456789/60605 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.791864
Chicago Manual of Style (16th Edition):
Patani, Hemalvi. “Investigating cancer-like DNA methylation patterns and genome stability upon reprogramming to naïve human pluripotency.” 2019. Doctoral Dissertation, Queen Mary, University of London. Accessed January 15, 2021.
http://qmro.qmul.ac.uk/xmlui/handle/123456789/60605 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.791864.
MLA Handbook (7th Edition):
Patani, Hemalvi. “Investigating cancer-like DNA methylation patterns and genome stability upon reprogramming to naïve human pluripotency.” 2019. Web. 15 Jan 2021.
Vancouver:
Patani H. Investigating cancer-like DNA methylation patterns and genome stability upon reprogramming to naïve human pluripotency. [Internet] [Doctoral dissertation]. Queen Mary, University of London; 2019. [cited 2021 Jan 15].
Available from: http://qmro.qmul.ac.uk/xmlui/handle/123456789/60605 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.791864.
Council of Science Editors:
Patani H. Investigating cancer-like DNA methylation patterns and genome stability upon reprogramming to naïve human pluripotency. [Doctoral Dissertation]. Queen Mary, University of London; 2019. Available from: http://qmro.qmul.ac.uk/xmlui/handle/123456789/60605 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.791864
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