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1.
Kadota, Léo.
Ecdysone-Regulated DNA Amplification in Sciara
coprophila.
Degree: Department of Molecular Biology, Cell Biology and
Biochemistry, 2017, Brown University
URL: https://repository.library.brown.edu/studio/item/bdr:733373/ 
► Abstract of ‘Ecdysone-Regulated DNA Amplification in Sciara coprophila’, by Léo Kadota, Sc.M., Brown University, May 2017. The eukaryotic genome contains thousands of origins (ORIs) of…
(more)
▼ Abstract of ‘Ecdysone-Regulated
DNA Amplification in
Sciara coprophila’, by Léo Kadota, Sc.M., Brown University, May
2017. The eukaryotic genome contains thousands of origins (ORIs) of
DNA replication, which are sequences where
DNA synthesis begins in
S phase of the cell cycle. The initiation of
DNA replication begins
in G1 phase in a tightly regulated process that is coordinated with
cell cycle progression. This ensures that an ORI fires no more than
once per cell cycle in order to evenly duplicate the genome that is
subsequently evenly divided to daughter cells during mitosis.
De-regulation of
DNA replication initiation can lead to
DNA
re-
replication, where an origin fires more than once during S
phase, producing more than the diploid copy number. Locus-specific
re-
replication, also called
DNA amplification, can lead to genomic
instability, a hallmark of certain human cancers.
DNA amplification
of tumorigenic genes has also been documented in the cells of
breast cancer tumors. It is therefore of general biological and
medical importance to understand the mechanisms leading to
DNA
amplification. It is hard to study the initiating events of
DNA
amplification in cancer cells. However,
DNA amplification occurs as
part of normal development during 4th larval instar in the larval
salivary gland chromosomes of the fungus gnat Sciara coprophila. In
human diseases,
DNA amplification is a rare event and is therefore
difficult to study experimentally. Sciara is a model organism that
provides a unique opportunity to elucidate the mechanisms of
DNA
amplification in vivo. In Sciara,
DNA amplification occurs at
eighteen amplicon loci distributed across its four chromosomes.
There is accumulating evidence that the steroid hormone ecdysone,
the master regulator of insect development, acts through the
ecdysone receptor as the amplification trigger for
DNA
amplification. This thesis describes experiments in which ecdysone
injection into pre-amplification stage Sciara larvae prematurely
induced
DNA amplification, as measured by quantitative PCR, at all
DNA amplicon loci. These observations support the hypothesis that
ecdysone and its receptor act as the amplification trigger in
Sciara. This thesis also details ongoing experiments aimed at
determining whether ecdysone induces the transcription of small
non-coding RNAs complementary to the amplicon origin, which could
recruit replisome machinery to the amplicon ORIs to promote
DNA
amplification.
Advisors/Committee Members: Gerbi, Susan (Advisor), Helfand, Stephen (Reader).
Subjects/Keywords: DNA replication
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APA (6th Edition):
Kadota, L. (2017). Ecdysone-Regulated DNA Amplification in Sciara
coprophila. (Thesis). Brown University. Retrieved from https://repository.library.brown.edu/studio/item/bdr:733373/
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):
Kadota, Léo. “Ecdysone-Regulated DNA Amplification in Sciara
coprophila.” 2017. Thesis, Brown University. Accessed March 02, 2021.
https://repository.library.brown.edu/studio/item/bdr:733373/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Kadota, Léo. “Ecdysone-Regulated DNA Amplification in Sciara
coprophila.” 2017. Web. 02 Mar 2021.
Vancouver:
Kadota L. Ecdysone-Regulated DNA Amplification in Sciara
coprophila. [Internet] [Thesis]. Brown University; 2017. [cited 2021 Mar 02].
Available from: https://repository.library.brown.edu/studio/item/bdr:733373/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Kadota L. Ecdysone-Regulated DNA Amplification in Sciara
coprophila. [Thesis]. Brown University; 2017. Available from: https://repository.library.brown.edu/studio/item/bdr:733373/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
East Carolina University
2.
Chmielewski, Jeffrey Patrick.
Drosophila Psf2 Has a Role In Chromosome
Condensation.
Degree: 2012, East Carolina University
URL: http://libres.uncg.edu/ir/listing.aspx?styp=ti&id=14010
► The condensation state of chromosomes is a critical parameter in multiple processes within the cell. Failures in the maintenance of appropriate condensation states may lead…
(more)
▼ The condensation state of chromosomes is a critical
parameter in multiple processes within the cell. Failures in the
maintenance of appropriate condensation states may lead to genomic
instability mis-expression of genes and a number of disease states.
During cell proliferation
replication of
DNA represents an ongoing
challenge for chromosome packaging as
DNA must be unpackaged for
replication and then faithfully repackaged. An integral member of
the
DNA replication machinery is the GINS complex which has been
shown to stabilize the CMG complex which is required for
processivity of the Mcm2-7 helicase complex during S phase. Through
examination of the phenotypes associated with a null mutation in
Psf2 a member of the evolutionarily conserved GINS complex we find
that Drosophila Psf2 likely has a role in establishing chromosome
condensation and that the defects associated with this
mis-condensation impact M phase progression genomic stability and
transcriptional regulation. ; Biology, Genetics, Chromosomes,
CMG, Condensation, Psf2
Advisors/Committee Members: Tim Christensen (advisor).
Subjects/Keywords: DNA replication; Chromosome replication; Drosophila
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APA (6th Edition):
Chmielewski, J. P. (2012). Drosophila Psf2 Has a Role In Chromosome
Condensation. (Masters Thesis). East Carolina University. Retrieved from http://libres.uncg.edu/ir/listing.aspx?styp=ti&id=14010
Chicago Manual of Style (16th Edition):
Chmielewski, Jeffrey Patrick. “Drosophila Psf2 Has a Role In Chromosome
Condensation.” 2012. Masters Thesis, East Carolina University. Accessed March 02, 2021.
http://libres.uncg.edu/ir/listing.aspx?styp=ti&id=14010.
MLA Handbook (7th Edition):
Chmielewski, Jeffrey Patrick. “Drosophila Psf2 Has a Role In Chromosome
Condensation.” 2012. Web. 02 Mar 2021.
Vancouver:
Chmielewski JP. Drosophila Psf2 Has a Role In Chromosome
Condensation. [Internet] [Masters thesis]. East Carolina University; 2012. [cited 2021 Mar 02].
Available from: http://libres.uncg.edu/ir/listing.aspx?styp=ti&id=14010.
Council of Science Editors:
Chmielewski JP. Drosophila Psf2 Has a Role In Chromosome
Condensation. [Masters Thesis]. East Carolina University; 2012. Available from: http://libres.uncg.edu/ir/listing.aspx?styp=ti&id=14010
University of Toronto
3.
Gallo, David.
Rad5 Recruitment and Function in the Saccharomyces cerevisiae Replication Stress Response.
Degree: PhD, 2018, University of Toronto
URL: http://hdl.handle.net/1807/91799
► DNA replication stress poses a significant threat to the genome integrity of actively dividing cells and is observed in many pathological human disorders. Replication stress…
(more)
▼ DNA replication stress poses a significant threat to the genome integrity of actively dividing cells and is observed in many pathological human disorders.
Replication stress is caused by endogenous or exogenous events that slow or block the
DNA replication machinery. All cells have an evolutionarily conserved
DNA replication stress response that slows down cell division until
DNA replication is complete and
DNA can be segregated. The Post-
Replication Repair (PRR) pathway allows tolerance of chemical- and UV-induced
DNA lesions in both an error-free and an error-prone manner. In classical PRR, PCNA monoubiquitination recruits translesion synthesis (TLS)
DNA polymerases that can replicate through lesions in a mutagenic manner. Polyubiquitination of PCNA by the ubiquitin ligase Rad5 initiates error-free PRR, using the sister chromatid as a template for
DNA synthesis in lieu of the lesion-containing strand. I find that Rad5 forms nuclear foci after exposure to types of
replication stress where
DNA base lesions are likely absent. In this study I characterize how Rad5 is recruited to nuclear foci and how Rad5 functions in lesion-less
replication stress. Using a genome-wide high-throughput screen I identified 23 genes that are required for robust Rad5 recruitment to nuclear foci. I revealed that the HSP40 chaperone Ydj1 in conjunction with the HSP70s Ssa1 and Ssb1 promote Rad5 relocalization and
replication stress resistance. To characterize Rad5 function in lesion-less
replication stress I monitored the genome-wide association of Rad5 using ChIP-seq and found it binds to sites near stressed
DNA replication forks. In addition to template switching activity at stressed
replication forks, Rad5 also recruits TLS polymerases to repair ssDNA gaps, preventing mitotic defects and chromosome breaks. My data indicates that Rad5 is the central effector of PRR at stressed
replication forks, where it promotes template switching and mutagenic repair of undamaged ssDNA that arises during physiological and exogenous
replication stress.
Advisors/Committee Members: Brown, Grant W, Biochemistry.
Subjects/Keywords: DNA replication; Replication stress; 0487
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APA (6th Edition):
Gallo, D. (2018). Rad5 Recruitment and Function in the Saccharomyces cerevisiae Replication Stress Response. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/91799
Chicago Manual of Style (16th Edition):
Gallo, David. “Rad5 Recruitment and Function in the Saccharomyces cerevisiae Replication Stress Response.” 2018. Doctoral Dissertation, University of Toronto. Accessed March 02, 2021.
http://hdl.handle.net/1807/91799.
MLA Handbook (7th Edition):
Gallo, David. “Rad5 Recruitment and Function in the Saccharomyces cerevisiae Replication Stress Response.” 2018. Web. 02 Mar 2021.
Vancouver:
Gallo D. Rad5 Recruitment and Function in the Saccharomyces cerevisiae Replication Stress Response. [Internet] [Doctoral dissertation]. University of Toronto; 2018. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1807/91799.
Council of Science Editors:
Gallo D. Rad5 Recruitment and Function in the Saccharomyces cerevisiae Replication Stress Response. [Doctoral Dissertation]. University of Toronto; 2018. Available from: http://hdl.handle.net/1807/91799
Hong Kong University of Science and Technology
4.
Xing, Li.
Structural studies of Cba3 and biochemical studies of human Orc6.
Degree: 2013, Hong Kong University of Science and Technology
URL: http://repository.ust.hk/ir/Record/1783.1-67034
;
https://doi.org/10.14711/thesis-b1254492
;
http://repository.ust.hk/ir/bitstream/1783.1-67034/1/th_redirect.html
► In the first part of this dissertation, the structural studies of Cba3 were described. Cellulose is the main structural component of the plant cell wall,…
(more)
▼ In the first part of this dissertation, the structural studies of Cba3 were described. Cellulose is the main structural component of the plant cell wall, the most abundant polysaccharide on Earth, and an important renewable resource. It consists of D-glucose residues linked by β-1,4-glycosidic bonds to form linear polymeric chains of over 10,000 glucose residues. Enzymatic conversion of cellulose to glucose is a complicated process and involves cooperative action of three enzymes: endoglucanas, exoglucanase, and cellobiase. Cba3, characterized from Cellulomonas biazotea in 2012, was a cellobiase catalyzing the breakdown reaction of one cellobiose into two glucoses. Previous sequence alignment studies reveal that Cba3 belongs to GH1 (Glycoside hydrolases 1) family and it is the first discovered GH1 β-glucosidase of C. biazotea. As the studies looking for high efficient cellobiase for industrial application are extensively increased, the structural studies of Cba3 would provide insights into the engineering of enzymes for enhanced protein stability and increased activity. On the other hand, as Cba3 presents different enzymatic activities towards cellobiose and lactose, the structural studies of Cba3 with its substrates would be greatly helpful for the elucidation of mechanism of substrate specificity. We expressed, purified and crystallized Cba3. We also resolved the three dimensional structure of Cba3. By the analysis of its structure, we found that Cba3 adopts classic (β/α)8 barrel fold. According to the experiment result, we make some primary discussion about its biological function. The second part of this dissertation describes the biochemical and structural studies of human Orc6 involved in origins recognition and binding during DNA replication initiation process. DNA replication initiation in eukaryotes requires a series of steps raging from origin recognition by ORC (origin recognition complex) to the activation of DNA helicase. The whole process is highly regulated to ensure that DNA is replicated a single round during each cell cycle which is crucial for the maintenance of the genome integrity. Through increasing studies on eukaryotes from yeast to human, it is indicated that the fundamental mechanism of DNA replication is well conserved. Orc6 is the least conserved of all ORC subunits. Sequence alignment between budding yeast and metazoan do not show statistically significant homology. In budding yeast, Orc6 is significantly larger than in metazoan species. Various studies show that Orc6 plays different functions in different species. In budding yeast Orc6 is dispensible for DNA binding in vitro. Further studies even report that yeast Orc6 interacts with Cdt1 and is involved in the loading of MCM helicase. In Xenopus and humans, Orc6 does not seem to be tightly associated with other core ORC subunits. Nevertheless, Orc6 is an integral part of Drosophila ORC and is essential for both DNA binding and replication both in vitro and in vivo. Moreover, Orc6 is reported to be implicated in cytokinesis…
Subjects/Keywords: Cellulomonas
; DNA replication
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APA (6th Edition):
Xing, L. (2013). Structural studies of Cba3 and biochemical studies of human Orc6. (Thesis). Hong Kong University of Science and Technology. Retrieved from http://repository.ust.hk/ir/Record/1783.1-67034 ; https://doi.org/10.14711/thesis-b1254492 ; http://repository.ust.hk/ir/bitstream/1783.1-67034/1/th_redirect.html
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):
Xing, Li. “Structural studies of Cba3 and biochemical studies of human Orc6.” 2013. Thesis, Hong Kong University of Science and Technology. Accessed March 02, 2021.
http://repository.ust.hk/ir/Record/1783.1-67034 ; https://doi.org/10.14711/thesis-b1254492 ; http://repository.ust.hk/ir/bitstream/1783.1-67034/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Xing, Li. “Structural studies of Cba3 and biochemical studies of human Orc6.” 2013. Web. 02 Mar 2021.
Vancouver:
Xing L. Structural studies of Cba3 and biochemical studies of human Orc6. [Internet] [Thesis]. Hong Kong University of Science and Technology; 2013. [cited 2021 Mar 02].
Available from: http://repository.ust.hk/ir/Record/1783.1-67034 ; https://doi.org/10.14711/thesis-b1254492 ; http://repository.ust.hk/ir/bitstream/1783.1-67034/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Xing L. Structural studies of Cba3 and biochemical studies of human Orc6. [Thesis]. Hong Kong University of Science and Technology; 2013. Available from: http://repository.ust.hk/ir/Record/1783.1-67034 ; https://doi.org/10.14711/thesis-b1254492 ; http://repository.ust.hk/ir/bitstream/1783.1-67034/1/th_redirect.html
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Aberdeen
5.
Hameister, Heike.
Mathematical models for DNA replication machinery.
Degree: PhD, 2012, University of Aberdeen
URL: https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152562400005941
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558612
► DNA replication and associated processes take place in all living organisms with the same constitutions. The knowledge of the duplication process, chromatin building and repair…
(more)
▼ DNA replication and associated processes take place in all living organisms with the same constitutions. The knowledge of the duplication process, chromatin building and repair mechanisms has increased explosively over the last years, but the complex interplay of different proteins and their mechanisms are not conceived properly. During DNA replication, the DNA has to be unpacked, duplicated and finally repacked into chromatin. These steps require different proteins, e.g. new histone proteins on demand to secure an error-free and undelayed DNA replication. This thesis includes different mathematical models for DNA replication, repair and chromatin formation, which are based on experimental results. Three models of chromatin formation provide a simplified description of histone gene expression and protein synthesis during G1/S/G2 phase and include the contribution of different regulatory elements. Furthermore, all models present two different mechanisms of regulation to test possible scenarios of newly synthesised histones and free DNA binding sites. The basic model presents a single histone gene, which codes for a single histone protein. The stem-loop binding protein (SLBP) acts as a master regulator, which is only present during S phase. Different analyses of early S-phase, over- and underexpressed replication and the down-regulation of SLBP proof the model under extreme conditions. This basic model serves as a template for further scenarios with several genes and different histone families. For this, a second model is realised to simulate imbalances in the histone mRNA synthesis and translation. Additionally, a third model tests a gene knock-out and mRNA silencing. The initial histone model is able to qualitatively reproduce experimental observations and shows basic regulatory principles. The adaptation with several genes and different histone families presents qualitatively different system responses for the discussed regulatory mechanisms and illustrates the ability to compensate the effect of mRNA silencing.
Subjects/Keywords: 572.8645; DNA replication
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APA (6th Edition):
Hameister, H. (2012). Mathematical models for DNA replication machinery. (Doctoral Dissertation). University of Aberdeen. Retrieved from https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152562400005941 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558612
Chicago Manual of Style (16th Edition):
Hameister, Heike. “Mathematical models for DNA replication machinery.” 2012. Doctoral Dissertation, University of Aberdeen. Accessed March 02, 2021.
https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152562400005941 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558612.
MLA Handbook (7th Edition):
Hameister, Heike. “Mathematical models for DNA replication machinery.” 2012. Web. 02 Mar 2021.
Vancouver:
Hameister H. Mathematical models for DNA replication machinery. [Internet] [Doctoral dissertation]. University of Aberdeen; 2012. [cited 2021 Mar 02].
Available from: https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152562400005941 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558612.
Council of Science Editors:
Hameister H. Mathematical models for DNA replication machinery. [Doctoral Dissertation]. University of Aberdeen; 2012. Available from: https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152562400005941 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558612
Cornell University
6.
Hartford, Suzanne.
The Role For Dna Replication And Repair Genes In Germ-Line Maintenance And Tumor Suppression.
Degree: PhD, Genetics, 2012, Cornell University
URL: http://hdl.handle.net/1813/29477
► : Faithful DNA replication and repair of DNA damage is important for prevention of disease and birth defects. My thesis work utilized reverse and forward…
(more)
▼ : Faithful
DNA replication and repair of
DNA damage is important for prevention of disease and birth defects. My thesis work utilized reverse and forward genetic approaches to identify novel genes involved in these processes. In one set of studies, I investigated the function of MCM9, a protein specific to multicellular eukaryotes that is related to subunits of the
DNA replicative helicase. Utilizing multiple mouse disruption alleles, I have shown MCM9 is dispensable for
DNA replication, however it has a role in germ-line stem cell maintenance and/or proliferation. Additionally, in the soma, Mcm9 mutation leads to increased cancer susceptibility, particularly hepatocellular carcinoma in males. The phenotypes of MCM9 mutant mice and cells suggest that MCM9 evolved a specialized but nonessential role in
DNA replication or
replication-linked quality-control mechanisms. In a second set of studies, I identified a hypomorphic allele of Fancm in a forward genetic screen for GIN mutations in mice. Fancm is a member of the Fanconi Anemia complementation group and facilitates repair of lesions at the
DNA replication fork. Similar to Mcm9, Fancm is required for producing a normal germ-line stem cell pool and for tumor suppression in the soma. Together, these genetic studies underscore the importance of accurate
DNA replication and repair of
replication-associated damage in mammalian reproduction and cancer.
Advisors/Committee Members: Schimenti, John C. (chair), Weiss, Robert S. (committee member), Tye, Bik-Kwoon (committee member).
Subjects/Keywords: DNA Replication; DNA Repair; mcm9
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APA (6th Edition):
Hartford, S. (2012). The Role For Dna Replication And Repair Genes In Germ-Line Maintenance And Tumor Suppression. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/29477
Chicago Manual of Style (16th Edition):
Hartford, Suzanne. “The Role For Dna Replication And Repair Genes In Germ-Line Maintenance And Tumor Suppression.” 2012. Doctoral Dissertation, Cornell University. Accessed March 02, 2021.
http://hdl.handle.net/1813/29477.
MLA Handbook (7th Edition):
Hartford, Suzanne. “The Role For Dna Replication And Repair Genes In Germ-Line Maintenance And Tumor Suppression.” 2012. Web. 02 Mar 2021.
Vancouver:
Hartford S. The Role For Dna Replication And Repair Genes In Germ-Line Maintenance And Tumor Suppression. [Internet] [Doctoral dissertation]. Cornell University; 2012. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1813/29477.
Council of Science Editors:
Hartford S. The Role For Dna Replication And Repair Genes In Germ-Line Maintenance And Tumor Suppression. [Doctoral Dissertation]. Cornell University; 2012. Available from: http://hdl.handle.net/1813/29477
7.
Sahashi, Ritsuko.
Cell biological and genetical studies on DNA replication enzyme and protein modification enzyme in Drosophila : ショウジョウバエ DNA 複製酵素及びタンパク質修飾酵素の細胞生物学・遺伝学的解析.
Degree: 博士（学術）, 2014, Kyoto Institute of Technology / 京都工芸繊維大学
URL: http://hdl.handle.net/10212/2155
DNAポリメラーゼα,δ,そしてε（polα, polδ,polε）はゲノムのDNA合成を行う酵素である。polαがRNAプライマーとそれに引き続く20〜30塩基のDNAを合成し、その後、polαと置き換わったpolδ,polεが、それぞれ、ラギング鎖、リーディング鎖の合成を行うことがわかっている。先行研究によりpolαと相互作用する因子の１つとして、ヒストンH4の20番目のリジン残基（H4-K20）をモノメチル化する酵素であるPr-Set7が同定された。第1章において、私はDNA複製とヒストンH4-K20メチル化との関係及び、polαとPr-Set7の相互作用について注目をした。翅原基特異的にショウジョウバエpolαの触媒サブユニットであるpolα180kDaサブユニット（dpolαp180）をノックダウンすると成虫翅の萎縮（atrophied wing表現型）が見られdpolαp180とdPr-Set7のダブルノックダウン系統では、atrophied wing表現型の増強が見られた。また、dpolαp180ノックダウン系統の翅原基でのDNA合成をモニターするためBrdU incorporation assayを行なった結果、BrdU ポジティブな細胞数に減少がみられ、dpolαp180とdPr-Set7のダブルノックダウン系統では、BrdU ポジティブな細胞数は、さらに減少した。これらのことより、個体レベルでも両者の機能的関連が示唆され、dPr-Set7がdpolαとの相互作用を介してDNA複製の制御に関与することが示唆された。また、dpolαp180をノックダウンした翅原基における抗H4-K20モノメチル化抗体を用いた免疫染色法の結果、H4-K20モノメチル化のシグナルが減少するこを明らかにした。このことより、Pr-Set7のメチル化活性制御にdpolαが重要な働きを担っている可能性が示された。 2章では、ショウジョウバエpolεの58 kDサブユニット（dpolεp58）の機能解析を行った。polεはヘテロ4量体タンパク質であることが報告されているが、ショウジョウバエでは、現在のところ、触媒サブユニットである255 kD (dpolεp255)サブユニットと、2番目サブユニットのdpolεp58サブユニットが同定されている。dpolεp58変異系統は、蛹で致死となり、3齢幼虫の成虫原基や唾腺が野生型と比較して小型化していた。これらのことからdpolεp58が組織の成長、細胞増殖および生存に必須であると示唆された。dpolεp58変異系統3齢幼虫の複眼原基では、形態形成溝の後極側におけるBrdUの取り込みが減少し、通常は増殖が停止し、分化している後極側の細胞でM期のシグナルが増加していた。S期の遅延が引き起こされたため、後極側の細胞におけるM期のシグナルが増加したと考えられる。これらの結果より、dpolεp58がS期の進行に関与している事が明らかとなった。また、唾腺の核が野生型と比較して小型化している事が観察され、dpolεp58のendoreplicationへの関与も示唆された。さらに、変異系統を用いて他の複製関連因子の抗体でウエスタン免疫ブロットを行った結果、複製開始因子であるdOrc2レベルの顕著な減少が見られた。このことからdpolεp58とdOrc2が細胞内で相互作用する可能性が示めされ、これらのことよりpolεが複製開始に関与することが示唆された。 第3章では、ショウジョウバエの発生において、私は、ショウジョウバエトランスグルタミナーゼ B（dTG-B）の働きを理解することを目的にdTG-B過剰発現系統を用いてその表現型の解析を行った。トランスグルタミナーゼ（TG）は、タンパク質間の架橋反応を触媒するタンパク質間翻訳後酵素で、様々な生物学的プロセスに関わっている。ショウジョウバエトランスグルタミナーゼの遺伝子は1種類で、A型とB型の2種類の転写産物が作られる。dTG-B過剰発現系統では、rough eye表現型と翅脈の過形成が観察された。これらの表現型は、先行研究により報告されているトランスグルタミナーゼA（dTG-A）の過剰発現系統において観察された表現型と同様であり、これらの結果からdTG-Aだけでなく、dTG-Bも複眼の形成と翅脈の形成において、その制御に関わっていることが示唆された。
Subjects/Keywords: DNA replication; DNA polymerase; Transglutaminase
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APA (6th Edition):
Sahashi, R. (2014). Cell biological and genetical studies on DNA replication enzyme and protein modification enzyme in Drosophila : ショウジョウバエ DNA 複製酵素及びタンパク質修飾酵素の細胞生物学・遺伝学的解析. (Thesis). Kyoto Institute of Technology / 京都工芸繊維大学. Retrieved from http://hdl.handle.net/10212/2155
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):
Sahashi, Ritsuko. “Cell biological and genetical studies on DNA replication enzyme and protein modification enzyme in Drosophila : ショウジョウバエ DNA 複製酵素及びタンパク質修飾酵素の細胞生物学・遺伝学的解析.” 2014. Thesis, Kyoto Institute of Technology / 京都工芸繊維大学. Accessed March 02, 2021.
http://hdl.handle.net/10212/2155.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sahashi, Ritsuko. “Cell biological and genetical studies on DNA replication enzyme and protein modification enzyme in Drosophila : ショウジョウバエ DNA 複製酵素及びタンパク質修飾酵素の細胞生物学・遺伝学的解析.” 2014. Web. 02 Mar 2021.
Vancouver:
Sahashi R. Cell biological and genetical studies on DNA replication enzyme and protein modification enzyme in Drosophila : ショウジョウバエ DNA 複製酵素及びタンパク質修飾酵素の細胞生物学・遺伝学的解析. [Internet] [Thesis]. Kyoto Institute of Technology / 京都工芸繊維大学; 2014. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/10212/2155.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Sahashi R. Cell biological and genetical studies on DNA replication enzyme and protein modification enzyme in Drosophila : ショウジョウバエ DNA 複製酵素及びタンパク質修飾酵素の細胞生物学・遺伝学的解析. [Thesis]. Kyoto Institute of Technology / 京都工芸繊維大学; 2014. Available from: http://hdl.handle.net/10212/2155
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Hong Kong University of Science and Technology
8.
Huang, Yining.
The role of hIpi3 in human DNA replication.
Degree: 2013, Hong Kong University of Science and Technology
URL: http://repository.ust.hk/ir/Record/1783.1-62314
;
https://doi.org/10.14711/thesis-b1254380
;
http://repository.ust.hk/ir/bitstream/1783.1-62314/1/th_redirect.html
► Ipi3 is required for cell viability in Saccharomyces cerevisiae. Yeast Ipi3 has been reported to be an essential component of the Rix1 complex (Rix1-Ipi1-Ipi3) that…
(more)
▼ Ipi3 is required for cell viability in Saccharomyces cerevisiae. Yeast Ipi3 has been reported to be an essential component of the Rix1 complex (Rix1-Ipi1-Ipi3) that is required for the processing of ITS2 sequences from 35S pre-rRNA in pre-60S ribosomal particles and for the initiation of DNA replication by interacting with ORC, MCM, Cdt1 and Cdc6. It has also been suggested that that human Ipi3 homolog plays a role in the assembly of the large ribosomal subunit in a computational analysis of large-scale protein-protein interactions. Human Ipi3 is WDR18 (WD repeat domain 18), which is a member of the WD repeat protein family, and it shares significant homology with the yeast Ipi3; the identity is 22% and similarity is 40%. Since yeast Ipi3 has an important role in the initiation of DNA replication, it is possibly that hIpi3 also functions in the initiation of DNA replication in human cells. We performed several experiments to support the hypothesis that hIpi3 is involved in the control of human DNA replication. First, knockdown of hIpi3 inhibited DNA replication, resulting in defective cell cycle progression. Second, the mRNA and protein levels of hIpi3 fluctuate in the cell cycle, just as some other pre-replicative (pre-RC) proteins do. Third, HA-tagged hIpi3 has been used to perform co-IP assay to identify hIpi3 interacting proteins. The results showed that hMcm7 interacted with hIpi3. Forth, hMcm7 and hCdc6 were reduced from chromatin after hIpi3 silencing, suggesting that hIpi3 is required for the chromatin association of the MCM complex. These results support that hIpi3 plays an important role in DNA replication in human cells.
Subjects/Keywords: DNA replication
; DNA-protein interactions
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Manager
APA (6th Edition):
Huang, Y. (2013). The role of hIpi3 in human DNA replication. (Thesis). Hong Kong University of Science and Technology. Retrieved from http://repository.ust.hk/ir/Record/1783.1-62314 ; https://doi.org/10.14711/thesis-b1254380 ; http://repository.ust.hk/ir/bitstream/1783.1-62314/1/th_redirect.html
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):
Huang, Yining. “The role of hIpi3 in human DNA replication.” 2013. Thesis, Hong Kong University of Science and Technology. Accessed March 02, 2021.
http://repository.ust.hk/ir/Record/1783.1-62314 ; https://doi.org/10.14711/thesis-b1254380 ; http://repository.ust.hk/ir/bitstream/1783.1-62314/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Huang, Yining. “The role of hIpi3 in human DNA replication.” 2013. Web. 02 Mar 2021.
Vancouver:
Huang Y. The role of hIpi3 in human DNA replication. [Internet] [Thesis]. Hong Kong University of Science and Technology; 2013. [cited 2021 Mar 02].
Available from: http://repository.ust.hk/ir/Record/1783.1-62314 ; https://doi.org/10.14711/thesis-b1254380 ; http://repository.ust.hk/ir/bitstream/1783.1-62314/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Huang Y. The role of hIpi3 in human DNA replication. [Thesis]. Hong Kong University of Science and Technology; 2013. Available from: http://repository.ust.hk/ir/Record/1783.1-62314 ; https://doi.org/10.14711/thesis-b1254380 ; http://repository.ust.hk/ir/bitstream/1783.1-62314/1/th_redirect.html
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Michigan State University
9.
Farnum, Gregory Alan.
Experimental and theoretical studies of the mitochondrial replisome.
Degree: 2013, Michigan State University
URL: http://etd.lib.msu.edu/islandora/object/etd:2966
► Thesis M.S. Michigan State University. Biochemistry and Molecular Biology 2013.
Despite the ubiquitous trend of increasing complexity in eukaryotes, the vital process of mtDNA replication…
(more)
▼ Thesis M.S. Michigan State University. Biochemistry and Molecular Biology 2013.
Despite the ubiquitous trend of increasing complexity in eukaryotes, the vital process of mtDNA replication has retained a simplistic, three component replisome consisting of the mtDNA Pol γ, mtSSB and the mtDNA replicative helicase. This minimal mitochondrial replisome resembles the bacteriophage T7 replisome and may even be simpler due to the apparent absence of a primase function in the N-terminal domain of the mtDNA replicative helicase. Interestingly, insects have retained the four cysteines of motif I which have been shown to bind zinc in T7, so an N-terminal construct (NTD) of Drosophila melanogaster mtDNA replicative helicase was designed containing the conserved residues. Purified fractions of the NTD construct contain an iron sulfur cluster, as determined by UV-Visible spectroscopy, as well as iron and sulfide determination. This work describes for the first time an iron sulfur cluster site in dm-mtDNA replicative helicase and evidence of weak DNA binding by the NTD using a FRET assay. Mutations in Pol γ represent a major cause of human mitochondrial diseases, especially those affecting the nervous system in adults and in children. More than 160 POLG1 disease mutations have been identified, which are nearly uniformly distributed along the length of the POLG1 sequence. Comprehensive literature analysis of the biochemical properties and disease characteristics of Pol γ in light of the crystal structure have revealed genotype-phenotype correlations that support the clustering of mutations into five functional modules in the catalytic core of Pol γ. Our results suggest that cluster prediction can be used to evaluate both the likely biochemical defects and the relative pathogenicity of new POLG variants.
Description based on online resource; title from PDF t.p. (viewed on Sept. 18, 2014)
Advisors/Committee Members: Kaguni, Laurie A, Geiger, James, Ferguson-Miller, Shelagh M.
Subjects/Keywords: Mitochondrial DNA; DNA replication; Biochemistry
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APA (6th Edition):
Farnum, G. A. (2013). Experimental and theoretical studies of the mitochondrial replisome. (Thesis). Michigan State University. Retrieved from http://etd.lib.msu.edu/islandora/object/etd:2966
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):
Farnum, Gregory Alan. “Experimental and theoretical studies of the mitochondrial replisome.” 2013. Thesis, Michigan State University. Accessed March 02, 2021.
http://etd.lib.msu.edu/islandora/object/etd:2966.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Farnum, Gregory Alan. “Experimental and theoretical studies of the mitochondrial replisome.” 2013. Web. 02 Mar 2021.
Vancouver:
Farnum GA. Experimental and theoretical studies of the mitochondrial replisome. [Internet] [Thesis]. Michigan State University; 2013. [cited 2021 Mar 02].
Available from: http://etd.lib.msu.edu/islandora/object/etd:2966.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Farnum GA. Experimental and theoretical studies of the mitochondrial replisome. [Thesis]. Michigan State University; 2013. Available from: http://etd.lib.msu.edu/islandora/object/etd:2966
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
10.
Badu-Nkansah, Akosua Agyeman.
Mechanisms of DNA Translocases in the Repair of Damaged Replication Forks.
Degree: PhD, Biochemistry, 2016, Vanderbilt University
URL: http://hdl.handle.net/1803/13267
► Genomic replication is a highly challenging task. The DNA replication machinery must precisely duplicate billions of base pairs while tolerating a multitude of obstacles including…
(more)
▼ Genomic
replication is a highly challenging task. The
DNA replication machinery must precisely duplicate billions of base pairs while tolerating a multitude of obstacles including damaged
DNA, collisions with transcriptional machineries, unusual
DNA structures and other difficult to replicate sequences. Many of these obstacles stall
replication forks and activate
replication stress responses that stabilize and restart persistently stalled forks. These mechanisms include fork remodeling to regress
replication forks into a chicken foot
DNA structure. Fork regression may facilitate
DNA repair or template switching to bypass the obstruction. Several members of the SNF2 family of
DNA-dependent ATPases including SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1), HLTF (Helicase like transcription factor) and ZRANB3 (Zinc finger Ran-binding protein 2- type containing 3) are
replication stress response proteins that catalyze fork remodeling including fork regression. The enzymatic activities of SMARCAL1 and HLTF are dependent on a SNF2 ATPase motor domain and a substrate recognition domain (SRD) that is thought to mediate binding to specific structures at stalled
replication forks. The SRD of SMARCAL1 is its HARP2 domain, which is required for SMARCAL1 binding to branched
DNA structures as well as its
DNA-dependent ATPase and fork regression activities. The SRD in HLTF is its HIRAN domain, which is unrelated in sequence and structure to the HARP domain and interacts with the exposed 3’ end of small
DNA flaps. The HIRAN domain is also important for HLTF mediated fork regression activity. Interestingly, unlike SMARCAL1 and HLTF, ZRANB3 contains a highly conserved ATP-dependent, substrate specific HNH endonuclease domain and catalyzes nuclease activity to branched
DNA substrates. How ZRANB3 catalyzes fork remodeling and endonuclease activities is unknown. This work identified a substrate recognition domain within ZRANB3 that is needed for it to recognize and bind forked
DNA structures, hydrolyze ATP, and catalyze fork remodeling and endonuclease activities. Importantly, this work provides a mechanistic understanding of how these enzymes operate within the
replication stress response to restart stalled
replication forks.
Advisors/Committee Members: Nicholas Reiter (committee member), Katherine Friedman (committee member), Brandt Eichman (committee member), Scott Hiebert (committee member), David Cortez (Committee Chair).
Subjects/Keywords: DNA Repair; Replication Stress; Replication Forks; DNA Replication; DNA Damage
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APA (6th Edition):
Badu-Nkansah, A. A. (2016). Mechanisms of DNA Translocases in the Repair of Damaged Replication Forks. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13267
Chicago Manual of Style (16th Edition):
Badu-Nkansah, Akosua Agyeman. “Mechanisms of DNA Translocases in the Repair of Damaged Replication Forks.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed March 02, 2021.
http://hdl.handle.net/1803/13267.
MLA Handbook (7th Edition):
Badu-Nkansah, Akosua Agyeman. “Mechanisms of DNA Translocases in the Repair of Damaged Replication Forks.” 2016. Web. 02 Mar 2021.
Vancouver:
Badu-Nkansah AA. Mechanisms of DNA Translocases in the Repair of Damaged Replication Forks. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1803/13267.
Council of Science Editors:
Badu-Nkansah AA. Mechanisms of DNA Translocases in the Repair of Damaged Replication Forks. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/13267
Portland State University
11.
Hamilton, Nicklas Alexander.
Use of Two-replisome Plasmids to Characterize How Chromosome Replication Completes.
Degree: MS(M.S.) in Biology, Biology, 2019, Portland State University
URL: https://pdxscholar.library.pdx.edu/open_access_etds/5064
► All living organisms need to accurately replicate their genome to survive. Genomic replication occurs in three phases; initiation, elongation, and completion. While initiation and…
(more)
▼ All living organisms need to accurately replicate their genome to survive. Genomic
replication occurs in three phases; initiation, elongation, and completion. While initiation and elongation have been extensively characterized, less is known about how
replication completes. In
Escherichia coli completion occurs at sites where two
replication forks converge and is proposed to involve the transiently bypass of the forks, before the overlapping sequences are resected and joined. The reaction requires RecBCD, and involves several other gene products including RecG, ExoI, and SbcDC but can occur independent of recombination or RecA. While several proteins are known to be involved, how they promote this reaction and the intermediates that arise remain uncharacterized.
In the first part of this work, I describe the construction of plasmid "mini-chromosomes" containing a bidirectional origin of
replication that can be used to examine the intermediates and factors required for the completion reaction. I verify that these substrates can be used to study the completion reaction by demonstrating that these plasmids require completion enzymes to propagate in cells. The completion enzymes are required for plasmids containing two-replisomes, but not one replisome, indicating that the substrate these enzymes act upon in vivo is specifically created when two
replication forks converge.
Completion events in
E. coli are localized to one of the six termination (
ter) sequences within the 400-kb terminus region due to the autoregulated action of Tus, which binds to
ter and inhibits
replication fork progression in an orientation-dependent manner. In the second part of this work, I examine how the presence of
ter sequences affect completion on the 2-replisome plasmid. I show that addition of
ter sequences modestly decreases the stability of the two-replisome plasmid and that this correlates with higher levels of abnormal, amplified molecules. The results support the idea that
ter sites are not essential to completion of
DNA replication; similar to what is seen on the chromosome.
Rec-B-C-D forms a helicase-nuclease complex that, in addition to completion, is also required for double-strand break repair in E. coli. RecBCD activity is altered upon encountering specific
DNA sequences, termed
chi, in a manner that promotes crossovers during recombinational processes. In the third part of this work, I demonstrate that the presence of
chi in a bidirectional plasmid model promotes the appearance of over-replicated linear molecules and that these products correlate with a reduced stability of the plasmid. The effect appears specific to plasmids containing two replisomes, as chi on the leading or lagging strand of plasmids containing one replisome had no-effect. The observation implies chi promotes a reaction that may encourage further synthesis during the completion reaction, and that at least on the mini-chromosomes substrates, this appears to…
Advisors/Committee Members: Justin Courcelle.
Subjects/Keywords: Chromosome replication; DNA replication – Research; Biology
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APA (6th Edition):
Hamilton, N. A. (2019). Use of Two-replisome Plasmids to Characterize How Chromosome Replication Completes. (Masters Thesis). Portland State University. Retrieved from https://pdxscholar.library.pdx.edu/open_access_etds/5064
Chicago Manual of Style (16th Edition):
Hamilton, Nicklas Alexander. “Use of Two-replisome Plasmids to Characterize How Chromosome Replication Completes.” 2019. Masters Thesis, Portland State University. Accessed March 02, 2021.
https://pdxscholar.library.pdx.edu/open_access_etds/5064.
MLA Handbook (7th Edition):
Hamilton, Nicklas Alexander. “Use of Two-replisome Plasmids to Characterize How Chromosome Replication Completes.” 2019. Web. 02 Mar 2021.
Vancouver:
Hamilton NA. Use of Two-replisome Plasmids to Characterize How Chromosome Replication Completes. [Internet] [Masters thesis]. Portland State University; 2019. [cited 2021 Mar 02].
Available from: https://pdxscholar.library.pdx.edu/open_access_etds/5064.
Council of Science Editors:
Hamilton NA. Use of Two-replisome Plasmids to Characterize How Chromosome Replication Completes. [Masters Thesis]. Portland State University; 2019. Available from: https://pdxscholar.library.pdx.edu/open_access_etds/5064
Vanderbilt University
12.
Guler, Gulfem Dilek.
Human DNA helicase B in replication fork surveillance and replication stress recovery.
Degree: PhD, Biological Sciences, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/15350
► Correct and faithful genome duplication is crucial for preserving genomic integrity. Genome duplication is, therefore, highly regulated through a complex network of proteins that accomplish…
(more)
▼ Correct and faithful genome duplication is crucial for preserving genomic integrity. Genome duplication is, therefore, highly regulated through a complex network of proteins that accomplish
DNA replication in addition to
DNA repair, as needed. Human
DNA helicase B (HDHB) was previously proposed to function in
DNA replication and
DNA damage response. Work presented in this dissertation aimed to gain insight into the cellular pathway(s) HDHB participates in, particularly in response to
replication stress. Contrary to previous studies where helicase-dead DHB inhibited
DNA replication, we did not observe any cell cycle or
DNA replication defect in HDHB silenced cells, suggesting that HDHB activity in
DNA replication can be compensated by other proteins in the absence of HDHB. On the other hand, HDHB silencing disrupted efficient recovery from
replication stress. HDHB silenced cells were capable of activating checkpoint signaling, suggesting a checkpoint-independent or downstream pathway for HDHB function. Consistent with a role in
replication stress response, HDHB accumulated on chromatin upon UV, hydroxyurea and camptothecin exposure in a time- and dose-dependent manner. We found that genotoxin-induced HDHB accumulation on chromatin is RPA-dependent. Biophysical and biochemical characterization revealed a direct physical interaction between RPA70N basic cleft and a conserved acidic motif in HDHB helicase domain. The interaction interface between HDHB and RPA70N is strikingly similar to the previously reported interaction interfaces of RPA70N and p53, ATRIP, Rad9 or Mre11. Site-directed mutagenesis of the HDHB-RPA70N interaction interface demonstrated its contribution to HDHB recruitment to chromatin upon genotoxin exposure. These results altogether implicate HDHB in
replication stress response.
Advisors/Committee Members: Ellen Fanning (committee member), Daniel Kaplan (committee member), David Cortez (committee member), Walter J. Chazin (committee member), James G. Patton (Committee Chair).
Subjects/Keywords: Replication protein A; RPA; DNA helicase; DNA replication; DNA repair; replication stress; HelB; HDHB
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APA (6th Edition):
Guler, G. D. (2012). Human DNA helicase B in replication fork surveillance and replication stress recovery. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15350
Chicago Manual of Style (16th Edition):
Guler, Gulfem Dilek. “Human DNA helicase B in replication fork surveillance and replication stress recovery.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed March 02, 2021.
http://hdl.handle.net/1803/15350.
MLA Handbook (7th Edition):
Guler, Gulfem Dilek. “Human DNA helicase B in replication fork surveillance and replication stress recovery.” 2012. Web. 02 Mar 2021.
Vancouver:
Guler GD. Human DNA helicase B in replication fork surveillance and replication stress recovery. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1803/15350.
Council of Science Editors:
Guler GD. Human DNA helicase B in replication fork surveillance and replication stress recovery. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/15350
Oregon State University
13.
Song, Shiwei.
Precursors for mitochondrial DNA replication : metabolic sources and relations to mutagenesis and human diseases.
Degree: PhD, Molecular And Cellular Biology, 2005, Oregon State University
URL: http://hdl.handle.net/1957/28973
► It is well known that the mitochondrial genome has a much higher spontaneous mutation rate than the nuclear genome. mtDNA mutations have been identified in…
(more)
▼ It is well known that the mitochondrial genome has a much higher spontaneous
mutation rate than the nuclear genome. mtDNA mutations have been identified in
association with many diseases and aging. mtDNA
replication continues throughout the
cell cycle, even in post-mitotic cells. Therefore, a constant supply of nucleotides is
required for
replication and maintenance of the mitochondrial genome. However, it is not
clear how dNTPs arise within mitochondria nor how mitochondrial dNTP pools are
regulated. Recent evidence suggests that abnormal mitochondrial nucleoside and
nucleotide metabolism is associated with several human diseases. Clearly, to uncover the
pathogenesis of these diseases and the mechanisms of mitochondrial mutagenesis,
information is needed regarding dNTP biosynthesis and maintenance within
mitochondria, and biochemical consequences of disordered mitochondrial dNTP
metabolism.
The studies described in this thesis provide important insight into these questions.
First, we found that a distinctive form of ribonucleotide reductase is associated with
mammalian liver mitochondria, indicating the presence of de novo pathway for dNTP
synthesis within mitochondria. Second, we found that long term thymidine treatment
could induce mtDNA deletions and the mitochondrial dNTP pool changes resulting from
thymidine treatment could account for the spectrum of mtDNA point mutations found in
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients. These results
support the proposed pathogenesis of this disease. Third, we found that normal
intramitochondrial dNTP pools in rat tissues are highly asymmetric, and in vitro fidelity
studies show that these imbalanced pools can stimulate base substitution and frameshift
mutations, with a substitution pattern that correlates with mitochondrial substitution
mutations in vivo. These findings suggest that normal intramitochondrial dNTP pool
asymmetries could contribute to mitochondrial mutagenesis and mitochondrial diseases.
Last, Amish lethal microcephaly (MCPHA) has been proposed to be caused by
insufficient transport of dNTPs into mitochondria resulting from a loss-of-function
mutation in the gene encoding a mitochondrial deoxynucleotide carrier (DNC). We found
that there are no significant changes of intramitochondrial dNTP levels in both a MCPHA
patient's lymphoblasts with a missense point mutation in Dnc gene and the homozygous
mutant cells extracted from Dnc gene knockout mouse embryos. These results do not
support the proposed pathogenesis of this disease and indicate that the DNC protein does
not play a crucial role in the maintenance of intramitochondrial dNTP pools.
Advisors/Committee Members: Mathews, Christopher K. (advisor), Pearson, George D. (committee member).
Subjects/Keywords: DNA replication
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APA (6th Edition):
Song, S. (2005). Precursors for mitochondrial DNA replication : metabolic sources and relations to mutagenesis and human diseases. (Doctoral Dissertation). Oregon State University. Retrieved from http://hdl.handle.net/1957/28973
Chicago Manual of Style (16th Edition):
Song, Shiwei. “Precursors for mitochondrial DNA replication : metabolic sources and relations to mutagenesis and human diseases.” 2005. Doctoral Dissertation, Oregon State University. Accessed March 02, 2021.
http://hdl.handle.net/1957/28973.
MLA Handbook (7th Edition):
Song, Shiwei. “Precursors for mitochondrial DNA replication : metabolic sources and relations to mutagenesis and human diseases.” 2005. Web. 02 Mar 2021.
Vancouver:
Song S. Precursors for mitochondrial DNA replication : metabolic sources and relations to mutagenesis and human diseases. [Internet] [Doctoral dissertation]. Oregon State University; 2005. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1957/28973.
Council of Science Editors:
Song S. Precursors for mitochondrial DNA replication : metabolic sources and relations to mutagenesis and human diseases. [Doctoral Dissertation]. Oregon State University; 2005. Available from: http://hdl.handle.net/1957/28973
Cornell University
14.
Dowicki, Michael.
The Wing Helix Domain Of Orc4 Is The Primary Determinant Of Dna Binding Specificity Of The Origin Recognition Complex.
Degree: PhD, Genetics, 2015, Cornell University
URL: http://hdl.handle.net/1813/40691
► The process of DNA replication is regulated to ensure that the entire genome is replicated only once during every cell division cycle. Eukaryotic DNA replication…
(more)
▼ The process of
DNA replication is regulated to ensure that the entire genome is replicated only once during every cell division cycle. Eukaryotic
DNA replication begins with the binding of the Origin
Replication Complex (ORC) to multiple
replication origins or Autonomously Replicating Sequences (ARSs) on every chromosome. The ORC machinery is conserved from fungal to mammalian systems, however the ARSs to which the ORC binds have diverged significantly. In the budding yeast S. cerevisiae the ORC binds a well-defined 17bp ACS, conversely in the fission yeast S. pombe ORC binds to AT rich sequences in a stochastic manner. Previously the
replication origins of the yeast K .lactis have been identified as a 50bp sequence necessary and largely sufficient for
replication. Through testing of plasmids constructed to contain either S. cerevisiae or K. lactis ARSs, it was found that each species is largely unable to replicate ARSs from the other species, indicating that the
replication machinery has significantly diverged to specifically recognize its own origin sequence. In this thesis, I am examining the role subunits of the ORC complex play in determining the binding specificity of the ORC complex. The ORC proteins contain a
DNA binding Winged Helix Domain in their C-termini. I have constructed S. cerevisiae strains containing chimeric ORC proteins which interact with the S. cerevisiae machinery while containing the K. lactis WHD. The chimeric ORC4 and ORC5 proteins fail to substitute for their respective endogenous proteins but the ORC4 chimera results in a dominant loss of silencing at the HMR locus, which is mediated by ORC. ChIP-Seq analysis showed that the chimeric strain binds to a K. lactis ACS at this locus and at several other distinct sites in the S. cerevisiae genome including the centromeres. Additionally the chimeric ORC4 demonstrates the ability to replicate plasmids containing a K. lactis ARS, unlike the wild type S. cerevisiae strain and S. cerevisiae containing a chimeric ORC5. This study suggests that the
DNA binding specificity for the S. cerevisiae ORC, K. lactis ORC and most likely ORCs in other fungi is primarily determined by the WHD of Orc4.
Advisors/Committee Members: Tye,Bik-Kwoon (chair), Gu,Zhenglong (committee member), Weiss,Robert S. (committee member).
Subjects/Keywords: DNA Replication; Origin Recognition Complex
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MLA ·
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APA (6th Edition):
Dowicki, M. (2015). The Wing Helix Domain Of Orc4 Is The Primary Determinant Of Dna Binding Specificity Of The Origin Recognition Complex. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/40691
Chicago Manual of Style (16th Edition):
Dowicki, Michael. “The Wing Helix Domain Of Orc4 Is The Primary Determinant Of Dna Binding Specificity Of The Origin Recognition Complex.” 2015. Doctoral Dissertation, Cornell University. Accessed March 02, 2021.
http://hdl.handle.net/1813/40691.
MLA Handbook (7th Edition):
Dowicki, Michael. “The Wing Helix Domain Of Orc4 Is The Primary Determinant Of Dna Binding Specificity Of The Origin Recognition Complex.” 2015. Web. 02 Mar 2021.
Vancouver:
Dowicki M. The Wing Helix Domain Of Orc4 Is The Primary Determinant Of Dna Binding Specificity Of The Origin Recognition Complex. [Internet] [Doctoral dissertation]. Cornell University; 2015. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1813/40691.
Council of Science Editors:
Dowicki M. The Wing Helix Domain Of Orc4 Is The Primary Determinant Of Dna Binding Specificity Of The Origin Recognition Complex. [Doctoral Dissertation]. Cornell University; 2015. Available from: http://hdl.handle.net/1813/40691
Cornell University
15.
Lee, Chanmi.
Interplay Between Mcm Helicase And Checkpoint Proteins Rescues Replication Fork Defects Of Mcm10.
Degree: 2009, Cornell University
URL: http://hdl.handle.net/1813/14066
► Mcm10 is essential in the initiation and elongation of DNA replication. It is implicated in the activation and stable assembly of various elongation factors such…
(more)
▼ Mcm10 is essential in the initiation and elongation of DNA replication. It is implicated in the activation and stable assembly of various elongation factors such as the MCM2-7 helicase, Cdc45, and polymerase alpha primase (Pol-alpha) at the replication fork based on its physical interactions with these proteins. Second site suppressors of two temperature labile mcm10 mutants have been identified and they have been shown to cluster in two regions of Mcm2 located at the interface of adjacent subunits of the hexameric MCM helicase. These dominant mcm2 suppressors restore viability to the mcm10 mutants without restoring the stability of Mcm10p, the interaction of Mcm10 with Mcm2, or the replication initiation defects of mcm10. Rather, they alleviate the elongation defect of mcm10 in that they suppress the HU and MMS sensitivity and the fork pausing phenotype of mcm10 as well as restore stability of Pol-alpha. This suppression requires the activity of genes involved in replication fork restart as well as key checkpoint regulators such as Rad53 and Mec1. Furthermore, stabilization of Polalpha is dependent on Mec1. These results suggest that at the restrictive temperature mcm10 causes destabilization of the replication fork that result in degradation of Pol-alpha. This fork defect is alleviated by the altered activity of the MCM helicase as well as the coordinated action of checkpoint proteins that stabilize replication forks.
Subjects/Keywords: DNA replication
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APA (6th Edition):
Lee, C. (2009). Interplay Between Mcm Helicase And Checkpoint Proteins Rescues Replication Fork Defects Of Mcm10. (Thesis). Cornell University. Retrieved from http://hdl.handle.net/1813/14066
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):
Lee, Chanmi. “Interplay Between Mcm Helicase And Checkpoint Proteins Rescues Replication Fork Defects Of Mcm10.” 2009. Thesis, Cornell University. Accessed March 02, 2021.
http://hdl.handle.net/1813/14066.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lee, Chanmi. “Interplay Between Mcm Helicase And Checkpoint Proteins Rescues Replication Fork Defects Of Mcm10.” 2009. Web. 02 Mar 2021.
Vancouver:
Lee C. Interplay Between Mcm Helicase And Checkpoint Proteins Rescues Replication Fork Defects Of Mcm10. [Internet] [Thesis]. Cornell University; 2009. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1813/14066.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lee C. Interplay Between Mcm Helicase And Checkpoint Proteins Rescues Replication Fork Defects Of Mcm10. [Thesis]. Cornell University; 2009. Available from: http://hdl.handle.net/1813/14066
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Cornell University
16.
Plys, Aaron.
Analysis Of The Movement Of Saccharomyces Cerevisiae Mismatch Repair Proteins On Dna.
Degree: PhD, Biochemistry, 2011, Cornell University
URL: http://hdl.handle.net/1813/30604
► Replication errors that escape DNA polymerase proof-reading activity are efficientl y recognized and repaired by conserved DNA mismatch repair factors. The overall result is a…
(more)
▼ Replication errors that escape
DNA polymerase proof-reading activity are efficientl y recognized and repaired by conserved
DNA mismatch repair factors. The overall result is a drastic reduction in deletion mutations. The mechanistic details of how mismatch repair proteins execute mismatch removal have not been elucidated. The aim of my thesis is to better understand how mismatch repair factors interact with
DNA in order to identify mismatch sites. My work reveals that the mismatch repair complex, MLH1-PMS1, has unique
DNA diffusion characteristics facilitated by structural features of the two subunits. Through bulk assays and total internal reflectance fluorescence microscopy (TIRFM), I found that MLH1PMS1 could independently bind
DNA and rapidly diffuse using the thermal energy of the system. Furthermore, MLH1-PMS1 was shown to be the first passively diffusing protein that could bypass stationary nucleosomes. In contrast, the
DNA diffusion activity of the mismatch recognition complex MSH2-MSH6 was blocked by nucleosomes. The timing and nature of mismatch repair is linked with
replication and is thus proposed that the differences seen for the two complexes have important implications for repair in the context of the chromatin state directly at the
replication fork. Each subunit of the MLH1-PMS1 complex is composed of two defined globular domains connected by an unstructured linker arm. The linker arms of the complex are proposed to facilitate topological
DNA binding and diffusion along
DNA in a hopping/stepping mechanism. I found that TEV protease cleavage within the linker arms of MLH1-PMS1 disrupted
DNA binding and mismatch repair in vitro and in vivo. Using a genetic mismatch repair assay I found that shortening of the linker arms in MLH1 had a drastic effect on function whereas similar changes in PMS1 had little or no effect. Purified truncated complexes were able to interact with
DNA and form ternary complexes with MSH2-MSH6 at a mismatch. Future studies should focus on the diffusion characteristic for these complexes. Together, my work has important implications for understanding how mismatch repair proteins can rapidly identify their targets in a chromatin landscape.
Advisors/Committee Members: Alani, Eric E (chair), Collins, Ruth N. (coChair), Weiss, Robert S. (committee member).
Subjects/Keywords: DNA mismatch repair; Replication; Cancer
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APA ·
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APA (6th Edition):
Plys, A. (2011). Analysis Of The Movement Of Saccharomyces Cerevisiae Mismatch Repair Proteins On Dna. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/30604
Chicago Manual of Style (16th Edition):
Plys, Aaron. “Analysis Of The Movement Of Saccharomyces Cerevisiae Mismatch Repair Proteins On Dna.” 2011. Doctoral Dissertation, Cornell University. Accessed March 02, 2021.
http://hdl.handle.net/1813/30604.
MLA Handbook (7th Edition):
Plys, Aaron. “Analysis Of The Movement Of Saccharomyces Cerevisiae Mismatch Repair Proteins On Dna.” 2011. Web. 02 Mar 2021.
Vancouver:
Plys A. Analysis Of The Movement Of Saccharomyces Cerevisiae Mismatch Repair Proteins On Dna. [Internet] [Doctoral dissertation]. Cornell University; 2011. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1813/30604.
Council of Science Editors:
Plys A. Analysis Of The Movement Of Saccharomyces Cerevisiae Mismatch Repair Proteins On Dna. [Doctoral Dissertation]. Cornell University; 2011. Available from: http://hdl.handle.net/1813/30604
Cornell University
17.
Li, Xin.
Aspects Of Eukaryotic Dna Replication, Repair And Recombination.
Degree: 2009, Cornell University
URL: http://hdl.handle.net/1813/13522
► The mechanism that replicates, maintains, and sometimes alters the DNA is most fundamental and important for life. Three processes (DNA Replication, Repair, and Recombination) that…
(more)
▼ The mechanism that replicates, maintains, and sometimes alters the DNA is most fundamental and important for life. Three processes (DNA Replication, Repair, and Recombination) that are involved in this mechanism are closely related and well conserved in evolution. In my Ph.D. studies, I have used the cross model-organism approach to investigate the molecular mechanisms of DNA replication stress induced cancer as well as meiosis disruption caused infertility. Mcm4Chaos3, which encodes a mutant subunit of the hexameric MCM helicase, was previously reported to cause genetic instability (GIN) in mice and predispose homozygous female mice to mammary adenocarcinomas. My results show that homozygous diploid yeast carrying the equivalent mutation are defective in replicating long terminal repeat (LTR) elements. The replication stress at these interspersed repeat sequences coupled with error prone repair is the source of GIN, which is the driving force for the acquisition of an accelerated proliferation (AP) phenotype with aneuploidy as byproducts. I showed that mutations unrelated to aneuploidy are the cause of the AP phenotype. Moreover, the fragility of LTR regions is dependent on ploidy. The LTRs are not vulnerable to replication stress in haploid yeast and mcm4Chaos3 haploids use other repair pathways without generating GIN. Therefore, the dichotomy of consequences of DNA replication stress and repair pathway choice stems from cell-type specific regulation of fragile sites. In mammalian meiosis, homologous chromosome synapsis is coupled with recombination. As in most eukaryotes, mammalian meiocytes have checkpoints that monitor the fidelity of these processes. I reported that the mouse ortholog (Trip13) of pachytene checkpoint 2 (PCH2), an essential component of the synapsis checkpoint in S. cerevisiae and C. elegans, is required after strand invasion for completing a subset of recombination events, but possibly not those destined to be crossovers (Li and Schimenti 2007). TRIP13-deficient mice exhibit spermatocyte death in pachynema and loss of oocytes around birth. The chromosomes of mutant spermatocytes synapse fully, yet retain several markers of recombination intermediates. This is the first model to separate recombination defects from asynapsis in mammalian meiosis. Surprisingly, we found no evidence for checkpoint function, suggesting different pachytene checkpoint mechanisms may be involved in different species (Li et al. 2008).
Subjects/Keywords: DNA Replication
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APA ·
Chicago ·
MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Li, X. (2009). Aspects Of Eukaryotic Dna Replication, Repair And Recombination. (Thesis). Cornell University. Retrieved from http://hdl.handle.net/1813/13522
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):
Li, Xin. “Aspects Of Eukaryotic Dna Replication, Repair And Recombination.” 2009. Thesis, Cornell University. Accessed March 02, 2021.
http://hdl.handle.net/1813/13522.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Li, Xin. “Aspects Of Eukaryotic Dna Replication, Repair And Recombination.” 2009. Web. 02 Mar 2021.
Vancouver:
Li X. Aspects Of Eukaryotic Dna Replication, Repair And Recombination. [Internet] [Thesis]. Cornell University; 2009. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1813/13522.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Li X. Aspects Of Eukaryotic Dna Replication, Repair And Recombination. [Thesis]. Cornell University; 2009. Available from: http://hdl.handle.net/1813/13522
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Hong Kong University of Science and Technology
18.
Cheung, Man Hei.
The role of NOC3 in DNA replication in human cells.
Degree: 2015, Hong Kong University of Science and Technology
URL: http://repository.ust.hk/ir/Record/1783.1-80225
;
https://doi.org/10.14711/thesis-b1514893
;
http://repository.ust.hk/ir/bitstream/1783.1-80225/1/th_redirect.html
► Noc3 (Nucleolar complex associated protein) was originally identified by a genetic screen in budding yeast Saccharomyces cerevisiae. It was reported that it plays crucial roles…
(more)
▼ Noc3 (Nucleolar complex associated protein) was originally identified by a genetic screen in budding yeast Saccharomyces cerevisiae. It was reported that it plays crucial roles in both ribosome biogenesis and DNA replication initiation. Its role in such important fundamental processes makes it essential for cell viability. It was shown to be needed for the maturation and nuclear export of the 40S subunit of ribosome. It also interacts with multiple replication initiation proteins including ORC (Origin recognition complex) and MCM (Minichromosome maintenance) and serves as an important bridge to facilitate the recruitment of Cdc6 (Cell division cycle) and Cdt1-MCM (Cdc10 dependent transcript) in pre-RC (Pre-replicative complex) assembly. Mainly by sequence homology, FAD24 (Factor for adipocyte differentiation, noted as NOC3 in this thesis) was identified as the human homolog of Noc3. It was shown that FAD24 is needed in the process of clonal expansion before differentiation occurs. Our data suggest that, NOC3 in human cells not only regulates adipocyte differentiation, but it is also a very important member of the pre-RC. A series of experiments have been performed and results suggest that NOC3 associates with chromatin, particularly replication origins, throughout the cell cycle; Knockdown of NOC3 abrogates pre-RC assembly, hence inhibiting DNA replication initiation and S-phase entry; Depletion of NOC3 leads to apoptosis before the cells can enter S-phase; NOC3 physically interacts with multiple subunits of both ORC and MCM. These all together strongly support our hypothesis that, NOC3 is one of the pre-RC members in human cells, just as its yeast homolog.
Subjects/Keywords: DNA replication
; Nuclear proteins
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APA ·
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Export
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APA (6th Edition):
Cheung, M. H. (2015). The role of NOC3 in DNA replication in human cells. (Thesis). Hong Kong University of Science and Technology. Retrieved from http://repository.ust.hk/ir/Record/1783.1-80225 ; https://doi.org/10.14711/thesis-b1514893 ; http://repository.ust.hk/ir/bitstream/1783.1-80225/1/th_redirect.html
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):
Cheung, Man Hei. “The role of NOC3 in DNA replication in human cells.” 2015. Thesis, Hong Kong University of Science and Technology. Accessed March 02, 2021.
http://repository.ust.hk/ir/Record/1783.1-80225 ; https://doi.org/10.14711/thesis-b1514893 ; http://repository.ust.hk/ir/bitstream/1783.1-80225/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Cheung, Man Hei. “The role of NOC3 in DNA replication in human cells.” 2015. Web. 02 Mar 2021.
Vancouver:
Cheung MH. The role of NOC3 in DNA replication in human cells. [Internet] [Thesis]. Hong Kong University of Science and Technology; 2015. [cited 2021 Mar 02].
Available from: http://repository.ust.hk/ir/Record/1783.1-80225 ; https://doi.org/10.14711/thesis-b1514893 ; http://repository.ust.hk/ir/bitstream/1783.1-80225/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Cheung MH. The role of NOC3 in DNA replication in human cells. [Thesis]. Hong Kong University of Science and Technology; 2015. Available from: http://repository.ust.hk/ir/Record/1783.1-80225 ; https://doi.org/10.14711/thesis-b1514893 ; http://repository.ust.hk/ir/bitstream/1783.1-80225/1/th_redirect.html
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Hong Kong University of Science and Technology
19.
Qin, Yan LIFS.
The role of hNOC3 in human DNA replication.
Degree: 2013, Hong Kong University of Science and Technology
URL: http://repository.ust.hk/ir/Record/1783.1-94452
;
https://doi.org/10.14711/thesis-b1266302
;
http://repository.ust.hk/ir/bitstream/1783.1-94452/1/th_redirect.html
► Noc3p (nucleolar complex-associated protein) is highly conserved in eukaryotes, and it plays a critical role in the initiation of DNA replication in budding yeast. Noc3p…
(more)
▼ Noc3p (nucleolar complex-associated protein) is highly conserved in eukaryotes, and it plays a critical role in the initiation of DNA replication in budding yeast. Noc3p interacts with ORC and MCM proteins and serves as an important link between ORC and other initiation proteins to facilitate the chromatin association of Cdc6 and MCM proteins. On the other hand, a Noc complex including Noc3p is specifically involved in the formation and nuclear export of the ribosomal 40S subunit. FAD24 (Factor for Adipocyte Differentiation) is the human homolog of Noc3p. It has been reported that hNOC3 is required for the regulation of DNA replication in cell proliferation as well as associated with cancer risk in the Chinese population. Overexpression of hNOC3 causes hyperplasia in adipose tissue and improves glucose metabolism. Our data show that knockdown of hNOC3 in HeLa cells leads to significant defects in the chromatin association of the other pre-replicative complex proteins including hMCM proteins and hCdc6, as well as a severe delay in the entry of S phase and apoptosis. In addition, hNOC3 binds to chromatin throughout the cell cycle and interacts with hORC and hMCM proteins, shown by the results of chromatin binding assay and yeast two-hybrid assay. Recent investigation of ChlP assay for hNOC3 on its binding to specific genomic regions reveal that hNOC3 associates with multiple well-known human replication origins. These data strongly suggest that hNOC3 plays an important role in the initiation of DNA replication, just as its yeast homolog.
Subjects/Keywords: DNA replication
; Cell cycle
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APA ·
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Export
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Manager
APA (6th Edition):
Qin, Y. L. (2013). The role of hNOC3 in human DNA replication. (Thesis). Hong Kong University of Science and Technology. Retrieved from http://repository.ust.hk/ir/Record/1783.1-94452 ; https://doi.org/10.14711/thesis-b1266302 ; http://repository.ust.hk/ir/bitstream/1783.1-94452/1/th_redirect.html
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):
Qin, Yan LIFS. “The role of hNOC3 in human DNA replication.” 2013. Thesis, Hong Kong University of Science and Technology. Accessed March 02, 2021.
http://repository.ust.hk/ir/Record/1783.1-94452 ; https://doi.org/10.14711/thesis-b1266302 ; http://repository.ust.hk/ir/bitstream/1783.1-94452/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Qin, Yan LIFS. “The role of hNOC3 in human DNA replication.” 2013. Web. 02 Mar 2021.
Vancouver:
Qin YL. The role of hNOC3 in human DNA replication. [Internet] [Thesis]. Hong Kong University of Science and Technology; 2013. [cited 2021 Mar 02].
Available from: http://repository.ust.hk/ir/Record/1783.1-94452 ; https://doi.org/10.14711/thesis-b1266302 ; http://repository.ust.hk/ir/bitstream/1783.1-94452/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Qin YL. The role of hNOC3 in human DNA replication. [Thesis]. Hong Kong University of Science and Technology; 2013. Available from: http://repository.ust.hk/ir/Record/1783.1-94452 ; https://doi.org/10.14711/thesis-b1266302 ; http://repository.ust.hk/ir/bitstream/1783.1-94452/1/th_redirect.html
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Gothenburg / Göteborgs Universitet
20.
Posse, Viktor.
Molecular insights into mitochondrial transcription and its role in DNA replication.
Degree: 2016, University of Gothenburg / Göteborgs Universitet
URL: http://hdl.handle.net/2077/50132
► The mitochondrion is an organelle of the eukaryotic cell responsible for the production of most of the cellular energy-carrying molecule adenosine triphosphate (ATP), through the…
(more)
▼ The mitochondrion is an organelle of the eukaryotic cell responsible for the production of most of the cellular energy-carrying molecule adenosine triphosphate (ATP), through the process of oxidative phosphorylation. The mitochondrion contains its own genome, a small circular DNA molecule (mtDNA), encoding essential subunits of the oxidative phosphorylation system. Initiation of mitochondrial transcription involves three proteins, the mitochondrial RNA polymerase, POLRMT, and its two transcription factors, TFAM and TFB2M. Even though the process of transcription has been reconstituted in vitro, a full molecular understanding is still missing. Initiation of mitochondrial DNA replication is believed to be primed by transcription prematurely terminated at a sequence known as CSBII. The mechanisms of replication initiation have however not been fully defined. In this thesis we have studied transcription and replication of mtDNA.
In the first part of this thesis we demonstrate that the transcription initiation machinery is recruited in discrete steps. Furthermore, we find that a large domain of POLRMT known as the N-terminal extension is dispensable for transcription initiation, and instead functions in suppressing initiation events from non-promoter DNA. Additionally we demonstrate that TFB2M is the last factor that is recruited to the initiation complex and that it induces melting of the mitochondrial promoters.
In this thesis we also demonstrate that POLRMT is a non-processive polymerase that needs the presence of the elongation factor TEFM for processive transcription. TEFM increases the affinity of POLRMT for an elongation-like RNA-DNA template and decreases the probability of premature transcription termination. Our data also suggest that TEFM might be of importance for mitochondrial replication initiation, since it affects termination at CSBII.
In the last part of this thesis we study the RNA-DNA hybrids (R-loops) that can be formed by the CSBII terminated transcript. We characterize these R-loops and demonstrate that they can be processed by RNaseH1 to form replicative primers that can be used by the mitochondrial replication machinery.
Subjects/Keywords: mitochondrion; mtDNA; transcription; DNA replication
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APA (6th Edition):
Posse, V. (2016). Molecular insights into mitochondrial transcription and its role in DNA replication. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/50132
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):
Posse, Viktor. “Molecular insights into mitochondrial transcription and its role in DNA replication.” 2016. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed March 02, 2021.
http://hdl.handle.net/2077/50132.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Posse, Viktor. “Molecular insights into mitochondrial transcription and its role in DNA replication.” 2016. Web. 02 Mar 2021.
Vancouver:
Posse V. Molecular insights into mitochondrial transcription and its role in DNA replication. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2016. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/2077/50132.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Posse V. Molecular insights into mitochondrial transcription and its role in DNA replication. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2016. Available from: http://hdl.handle.net/2077/50132
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Hong Kong University of Science and Technology
21.
Tsang, Yiu Huen.
The identification of phosphatases important for mitosis and replicative stress response.
Degree: 2011, Hong Kong University of Science and Technology
URL: http://repository.ust.hk/ir/Record/1783.1-7286
;
https://doi.org/10.14711/thesis-b1160524
;
http://repository.ust.hk/ir/bitstream/1783.1-7286/1/th_redirect.html
► In every cell division cycle, daughter cells carry the same genomic information as their parental cell. Maintenance of the genomic stability requires several checkpoints that…
(more)
▼ In every cell division cycle, daughter cells carry the same genomic information as their parental cell. Maintenance of the genomic stability requires several checkpoints that function at different stages of the cell cycle. These checkpoints halt cell cycle progression to allow cells to have the time to correct errors. Cells with defective checkpoints may allow errors to accumulate and eventually promote tumorigenesis. Therefore, identifying components of the checkpoints is important for a better understanding of how genome stability is maintained. Protein phosphorylation is important in many cellular processes, including normal cell cycle progression and checkpoint regulation. While protein kinases involved in cell cycle control and checkpoints have been studied extensively, the protein phosphatases involving in the processes are less understood. To identify novel phosphatases important for mitosis and replicative stress responses, RNA interference screens targeting the all phosphatases in the human genome were performed. A short-hairpin RNA library against the human phosphatome was generated. These screens were designed to identify phosphatases that, when depleted, affected mitotic progression and survival after replicative stress. A large number of phosphatases were identified to be required for proper mitotic progression. Several phosphatases, including the non-receptor type protein tyrosine phosphatase PTPN11 (SHP2), were identified to be important for survival after replicative stress. Cells were more susceptible to hydroxyurea-induced cell death in the absence of SHP2. Furthermore, SHP2 is required for cell survival after other DNA damaging agents, indicating that SHP2 is critical for different DNA stresses. Collectively, these studies underscore the importance of protein phosphatases in cell cycle control.
Subjects/Keywords: Phosphatases
; DNA replication
; Mitosis
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APA (6th Edition):
Tsang, Y. H. (2011). The identification of phosphatases important for mitosis and replicative stress response. (Thesis). Hong Kong University of Science and Technology. Retrieved from http://repository.ust.hk/ir/Record/1783.1-7286 ; https://doi.org/10.14711/thesis-b1160524 ; http://repository.ust.hk/ir/bitstream/1783.1-7286/1/th_redirect.html
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):
Tsang, Yiu Huen. “The identification of phosphatases important for mitosis and replicative stress response.” 2011. Thesis, Hong Kong University of Science and Technology. Accessed March 02, 2021.
http://repository.ust.hk/ir/Record/1783.1-7286 ; https://doi.org/10.14711/thesis-b1160524 ; http://repository.ust.hk/ir/bitstream/1783.1-7286/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Tsang, Yiu Huen. “The identification of phosphatases important for mitosis and replicative stress response.” 2011. Web. 02 Mar 2021.
Vancouver:
Tsang YH. The identification of phosphatases important for mitosis and replicative stress response. [Internet] [Thesis]. Hong Kong University of Science and Technology; 2011. [cited 2021 Mar 02].
Available from: http://repository.ust.hk/ir/Record/1783.1-7286 ; https://doi.org/10.14711/thesis-b1160524 ; http://repository.ust.hk/ir/bitstream/1783.1-7286/1/th_redirect.html.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Tsang YH. The identification of phosphatases important for mitosis and replicative stress response. [Thesis]. Hong Kong University of Science and Technology; 2011. Available from: http://repository.ust.hk/ir/Record/1783.1-7286 ; https://doi.org/10.14711/thesis-b1160524 ; http://repository.ust.hk/ir/bitstream/1783.1-7286/1/th_redirect.html
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Princeton University
22.
Haye, Joanna E.
DYNAMICS OF THE MISMATCH REPAIR COMPLEXES DURING DNA REPLICATION
.
Degree: PhD, 2014, Princeton University
URL: http://arks.princeton.edu/ark:/88435/dsp01vm40xt80m
► DNA mismatch repair (MMR) functions mainly to correct mispaired bases that escape the proofreading activity of the DNA polymerase during replication. Defects in MMR genes…
(more)
▼ DNA mismatch repair (MMR) functions mainly to correct mispaired bases that escape the proofreading activity of the
DNA polymerase during
replication. Defects in MMR genes have been linked to compromised genome stability and diseases including cancer. MMR is a highly conserved process and the yeast Saccharomyces cerevisiae is an ideal model organism to explore aspects of MMR because of the ease of manipulation and homology to the human system. MMR initiates when a mismatch in the
DNA helix is recognized by MutS homologs. Subsequent events include excision of the error-containing strand followed by re-synthesis. A critical step in this process is directing repair to the newly synthesized strand, which requires a strand discrimination signal. Current data suggest that transient discontinuities in the
DNA backbone, known as nicks, generated during
replication serve as the strand discrimination signal. Additionally, histones have the capacity to block mismatch recognition and are known to rapidly assemble behind the
replication fork. Thus, there must be a short window of opportunity for the MutS homologs to scan for mismatches and access the strand discrimination signals during
replication. To address these unresolved issues, we hypothesize that the MMR machinery tracks with the replisome to allow for efficient scanning and access to the strand discrimination signal. We employed chromatin immunoprecipitation and
DNA tiling microarrays (ChIP-chip) to determine the distribution of the eukaryotic MutS complexes during
replication. The data indicate that during S-phase of the cell cycle MutS binds origins of
replication and shows bi-directional occupancy of regions flanking the origins over time with timing consistent with fork progression. Importantly, MutS displays the same origin binding and spreading pattern as the leading strand
DNA polymerase over multiple experiments. In sum, our data supports the hypothesis of the MMR machinery tracking with the replisome.
There are two MutS complexes that occur in eukaryotes, MutSα (Msh2/Msh6) and MutSβ (Msh2/Msh3). Both complexes recognize the different types of mismatches that arise during
DNA replication. Reporter constructs have traditionally been utilized to assay the types of mismatches targeted by each complex. With the availability of new techniques, we can now analyze the functions of MutSα and MutSβ on a genome wide scale. In this work, we used next generation sequencing to determine the mutation spectra in strains lacking MSH2, MSH3 or MSH6. Our studies confirm the findings of previous genetic experiments that MutSα and MutSβ are functionally redundant for repair at HPRs; however, each complex is essential for ~6-7% of the mismatches generated during
replication. In this work, we provide evidence that both complexes should be in the vicinity of the replisome to ensure that majority of the mutations can be avoided during
replication.
Advisors/Committee Members: Gammie, Alison E (advisor), Rose, Mark D (advisor).
Subjects/Keywords: DNA mismatch repair;
Replication
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APA (6th Edition):
Haye, J. E. (2014). DYNAMICS OF THE MISMATCH REPAIR COMPLEXES DURING DNA REPLICATION
. (Doctoral Dissertation). Princeton University. Retrieved from http://arks.princeton.edu/ark:/88435/dsp01vm40xt80m
Chicago Manual of Style (16th Edition):
Haye, Joanna E. “DYNAMICS OF THE MISMATCH REPAIR COMPLEXES DURING DNA REPLICATION
.” 2014. Doctoral Dissertation, Princeton University. Accessed March 02, 2021.
http://arks.princeton.edu/ark:/88435/dsp01vm40xt80m.
MLA Handbook (7th Edition):
Haye, Joanna E. “DYNAMICS OF THE MISMATCH REPAIR COMPLEXES DURING DNA REPLICATION
.” 2014. Web. 02 Mar 2021.
Vancouver:
Haye JE. DYNAMICS OF THE MISMATCH REPAIR COMPLEXES DURING DNA REPLICATION
. [Internet] [Doctoral dissertation]. Princeton University; 2014. [cited 2021 Mar 02].
Available from: http://arks.princeton.edu/ark:/88435/dsp01vm40xt80m.
Council of Science Editors:
Haye JE. DYNAMICS OF THE MISMATCH REPAIR COMPLEXES DURING DNA REPLICATION
. [Doctoral Dissertation]. Princeton University; 2014. Available from: http://arks.princeton.edu/ark:/88435/dsp01vm40xt80m
University of Minnesota
23.
Becker, Jordan.
Postreplicative repair is an integral component of lagging strand DNA replication and a suppressor of replication stress.
Degree: PhD, Biochemistry, Molecular Bio, and Biophysics, 2016, University of Minnesota
URL: http://hdl.handle.net/11299/188873
► Cell division is a basic requirement for the propagation of all organisms. This process begins with a parental cell which divides, leaving two daughter cells.…
(more)
▼ Cell division is a basic requirement for the propagation of all organisms. This process begins with a parental cell which divides, leaving two daughter cells. Prior to division, it is necessary for the parental cell to generate a precise duplicate of its genetic material via the process of DNA replication, so that each resulting daughter segregates with a full genetic complement. Errors that occur during this process are thus inherited as mutations by the daughter cells and perpetuated in each subsequent generation along that lineage. Because an estimated 10,000 trillion cell divisions occur in the average lifetime of a human being, it is imperative that this process occurs with a minimum of errors [Quammen 2008]. In the event of difficulty or error, a network of repair and checkpoint pathways has arisen to facilitate the completion of replication with a minimum of inherited mutations [Myung et al. 2001]. The high level of conservation in these replication, repair and checkpoint pathways has allowed us to utilize relatively simple model organisms, such as S. cerevisiae (budding yeast), to better understand how these processes are carried out in more complex metazoan systems. My research has focused on one such group of pathways collectively referred to as postreplicative repair or “PRR” [Chen et al. 2011]. PRR is activated in response to a variety of stressors, which cause difficulty for the replication program and mitigates their impact on genome integrity. The findings included in this dissertation expand our knowledge of stressors, which impact the usage of PRR pathways and moreover describe PRR as an integral component of lagging strand DNA replication.
Subjects/Keywords: DNA replication; Okazaki fragment; Rad27
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APA (6th Edition):
Becker, J. (2016). Postreplicative repair is an integral component of lagging strand DNA replication and a suppressor of replication stress. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/188873
Chicago Manual of Style (16th Edition):
Becker, Jordan. “Postreplicative repair is an integral component of lagging strand DNA replication and a suppressor of replication stress.” 2016. Doctoral Dissertation, University of Minnesota. Accessed March 02, 2021.
http://hdl.handle.net/11299/188873.
MLA Handbook (7th Edition):
Becker, Jordan. “Postreplicative repair is an integral component of lagging strand DNA replication and a suppressor of replication stress.” 2016. Web. 02 Mar 2021.
Vancouver:
Becker J. Postreplicative repair is an integral component of lagging strand DNA replication and a suppressor of replication stress. [Internet] [Doctoral dissertation]. University of Minnesota; 2016. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/11299/188873.
Council of Science Editors:
Becker J. Postreplicative repair is an integral component of lagging strand DNA replication and a suppressor of replication stress. [Doctoral Dissertation]. University of Minnesota; 2016. Available from: http://hdl.handle.net/11299/188873
University of Arizona
25.
Langston, Rachel Elizabeth.
DNA Replication Defects in the Telomere Induce Chromosome Instability in a Single Cell Cycle
.
Degree: 2016, University of Arizona
URL: http://hdl.handle.net/10150/622910
► Errors in DNA replication can cause chromosome instability and gross chromosomal rearrangements (GCRs). For my thesis work I investigate how chromosome instability can originate in…
(more)
▼ Errors in
DNA replication can cause chromosome instability and gross chromosomal rearrangements (GCRs). For my thesis work I investigate how chromosome instability can originate in the telomere. Here I report how defects in Cdc13, a telomere specific protein, lead to chromosome instability and GCRs in Saccharomyces cerevisiae. Using a temperature sensitive mutant of Cdc13, I find that cdc13-induced instability can be induced in a single cell cycle and synergizes with
replication stress (dNTP depletion via hydroxyurea). Additionally, I find that Cdc13 has to be functional during the cell’s S phase to suppress chromosome instability. Further genetic analysis suggests that that cdc13-induced chromosome instability depends on the generation of single stranded (ss)
DNA, but not on the activity of canonical double strand break (DSB) repair pathways such as homologous recombination or non-homologous end joining. Finally, I demonstrate that telomeric unstable chromosomes can later progress and trigger rearrangements at centromeric loci. This system, using the conditional nature of the cdc13 mutation, promises a more complex analysis of the ontogeny of chromosome instability: in this case from errors semi-conservative
DNA replication through the telomere to the formation and resolution of unstable chromosomes.
Advisors/Committee Members: Weinert, Ted (advisor), Weinert, Ted (committeemember), Capaldi, Andrew (committeemember), Bolger, Tim (committeemember), Beilstein, Mark (committeemember).
Subjects/Keywords: DNA replication;
telomere;
Chromosome instability
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Export
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APA (6th Edition):
Langston, R. E. (2016). DNA Replication Defects in the Telomere Induce Chromosome Instability in a Single Cell Cycle
. (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/622910
Chicago Manual of Style (16th Edition):
Langston, Rachel Elizabeth. “DNA Replication Defects in the Telomere Induce Chromosome Instability in a Single Cell Cycle
.” 2016. Doctoral Dissertation, University of Arizona. Accessed March 02, 2021.
http://hdl.handle.net/10150/622910.
MLA Handbook (7th Edition):
Langston, Rachel Elizabeth. “DNA Replication Defects in the Telomere Induce Chromosome Instability in a Single Cell Cycle
.” 2016. Web. 02 Mar 2021.
Vancouver:
Langston RE. DNA Replication Defects in the Telomere Induce Chromosome Instability in a Single Cell Cycle
. [Internet] [Doctoral dissertation]. University of Arizona; 2016. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/10150/622910.
Council of Science Editors:
Langston RE. DNA Replication Defects in the Telomere Induce Chromosome Instability in a Single Cell Cycle
. [Doctoral Dissertation]. University of Arizona; 2016. Available from: http://hdl.handle.net/10150/622910
University of Waterloo
26.
DaSilva, Lance.
Functional Characterization of the Origin Recognition Complex (ORC) in S. cerevisiae.
Degree: 2008, University of Waterloo
URL: http://hdl.handle.net/10012/3518
► The origin recognition complex (Orc1-6) plays a fundamental role in the initiation of DNA replication by binding replication origins throughout the budding yeast cell cycle.…
(more)
▼ The origin recognition complex (Orc1-6) plays a fundamental role in the initiation of DNA replication by binding replication origins throughout the budding yeast cell cycle. ORC acts as a scaffold for the assembly of the pre-replicative complex (pre-RC) factors Cdc6, Cdt1 and a replicative helicase, the minichromosome maintenance (MCM2-7) complex in G1 phase. Upon assembly, origins are then said to be “licensed” for DNA replication. Previous models of pre-RC assembly and function have predicted that once MCMs have been loaded onto chromatin, ORC and Cdc6 are no longer required for DNA replication. In contrast, data from our lab strongly suggest a role for Orc6 in the maintenance of MCMs after pre-RC formation. Orc6 was found to be required for the chromatin maintenance of Mcm2 and more specifically, chromatin immunoprecipitation (ChIP) analysis demonstrated that Orc6 was necessary for the continued origin association of MCM proteins in late G1 at the early-firing origin ARS1, and the late-firing origin ARS609. It was also determined that after destabilization in the absence of Orc6, the pre-RC could be reassembled and facilitate DNA replication in late G1 after Orc6 expression had been turned back on. Interestingly, the clamp loading protein Cdc6 was also discovered to be essential to the maintenance of MCM proteins on bulk chromatin and at ARS1.
Subjects/Keywords: DNA Replication
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Export
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Manager
APA (6th Edition):
DaSilva, L. (2008). Functional Characterization of the Origin Recognition Complex (ORC) in S. cerevisiae. (Thesis). University of Waterloo. Retrieved from http://hdl.handle.net/10012/3518
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):
DaSilva, Lance. “Functional Characterization of the Origin Recognition Complex (ORC) in S. cerevisiae.” 2008. Thesis, University of Waterloo. Accessed March 02, 2021.
http://hdl.handle.net/10012/3518.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
DaSilva, Lance. “Functional Characterization of the Origin Recognition Complex (ORC) in S. cerevisiae.” 2008. Web. 02 Mar 2021.
Vancouver:
DaSilva L. Functional Characterization of the Origin Recognition Complex (ORC) in S. cerevisiae. [Internet] [Thesis]. University of Waterloo; 2008. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/10012/3518.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
DaSilva L. Functional Characterization of the Origin Recognition Complex (ORC) in S. cerevisiae. [Thesis]. University of Waterloo; 2008. Available from: http://hdl.handle.net/10012/3518
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Georgia
27.
Reiff, Sarah Baker.
The maintenance and replication of the apicoplast genome in Toxoplasma gondii.
Degree: 2014, University of Georgia
URL: http://hdl.handle.net/10724/28084
► The phylum Apicomplexa comprises a group of intracellular parasites of significant global health and economic concern. Most apicomplexan parasites possess a relict plastid organelle, which…
(more)
▼ The phylum Apicomplexa comprises a group of intracellular parasites of significant global health and economic concern. Most apicomplexan parasites possess a relict plastid organelle, which no longer performs photosynthesis but still retains
important metabolic functions. This organelle, known as the apicoplast, also contains its own genome which is required for parasite viability. The apicoplast and its genome have been shown to be useful as therapeutic targets. However, limited information
is available about the replication and maintenance of plastid DNA, not just in apicomplexan parasites but also in plants and algae. Here we use the genetic tools available in the model apicomplexan Toxoplasma gondii to examine putative apicoplast DNA
replication and condensation factors, including homologs of DNA polymerase I, single-stranded DNA binding protein, DNA gyrase, and the histone-like protein HU. We confirm targeting to the apicoplast of these candidates, which are all encoded in the
nucleus and must be imported. We created a genetic knockout of the Toxoplasma HU gene, which encodes a homolog of a bacterial protein that helps condense the bacterial nucleoid. We show that loss of HU in Toxoplasma results in a strong decrease in
apicoplast DNA content, accompanied by biogenesis and segregation defects of the organelle. We were also interested in examining the roles of enzymes that might be more directly involved in DNA replication. To this end we constructed conditional mutants
of the Toxoplasma gyrase B homolog and the DNA polymerase I homolog, which appears to be the result of a gene fusion and contains multiple different catalytic domains. We find that these proteins are essential to the parasite and required for apicoplast
DNA replication. Together these data highlight the importance of the apicoplast DNA in apicomplexan cell biology and increase our understanding of plastid genome biology.
Subjects/Keywords: Apicoplast genome; DNA replication; HU
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Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Reiff, S. B. (2014). The maintenance and replication of the apicoplast genome in Toxoplasma gondii. (Thesis). University of Georgia. Retrieved from http://hdl.handle.net/10724/28084
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):
Reiff, Sarah Baker. “The maintenance and replication of the apicoplast genome in Toxoplasma gondii.” 2014. Thesis, University of Georgia. Accessed March 02, 2021.
http://hdl.handle.net/10724/28084.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Reiff, Sarah Baker. “The maintenance and replication of the apicoplast genome in Toxoplasma gondii.” 2014. Web. 02 Mar 2021.
Vancouver:
Reiff SB. The maintenance and replication of the apicoplast genome in Toxoplasma gondii. [Internet] [Thesis]. University of Georgia; 2014. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/10724/28084.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Reiff SB. The maintenance and replication of the apicoplast genome in Toxoplasma gondii. [Thesis]. University of Georgia; 2014. Available from: http://hdl.handle.net/10724/28084
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
28.
Wells, Christina Elizabeth.
Elucidating the mechanism of action of selective histone deacetylase inhibitors in cancer.
Degree: PhD, Biochemistry, 2013, Vanderbilt University
URL: http://hdl.handle.net/1803/10934
► Given the fundamental roles of histone deacetylases (HDACs) in the regulation of DNA repair, replication, transcription and chromatin structure, it is fitting that therapies targeting…
(more)
▼ Given the fundamental roles of histone deacetylases (HDACs) in the regulation of
DNA repair,
replication, transcription and chromatin structure, it is fitting that therapies targeting HDAC activities are now being explored as anti-cancer agents. In fact, two histone deacetylase inhibitors (HDIs), SAHA and Depsipeptide, are FDA approved for single-agent treatment of refractory cutaneous T cell lymphoma (CTCL). An important target of these HDIs, histone deacetylase 3 (HDAC3), regulates processes such as
DNA repair, metabolism, and tumorigenesis through the regulation of chromatin structure and gene expression. The data in this dissertation show that HDAC3 inhibition using a selective inhibitor, RGFP966, resulted in decreased cell growth in CTCL cell lines due to increased apoptosis that was associated with
DNA damage and impaired S phase progression. Interestingly, through isolation of proteins on nascent
DNA (iPOND), HDAC3 was associated with chromatin and is present at and around
DNA replication forks.
DNA fiber labeling analysis showed that inhibition of HDAC3 resulted in a significant reduction in
DNA replication fork velocity within the first hour of drug treatment. This work also explores whether inhibition of HDACs 1/2 or HDACs 1-3 using selective inhibitors (RGFP233 and RGFP963 respectively) affects
DNA replication.
DNA fiber labeling analysis showed that treatment with either of these inhibitors resulted in reduction in
DNA replication fork velocity. These results suggest that selective inhibition of HDAC3, HDACs 1/2, or HDACs 1-3 could be useful in treatment of CTCL by disrupting
DNA replication of the rapidly cycling tumor cells, ultimately leading to cell death.
Advisors/Committee Members: Utpal Dave (committee member), Kevin Schey (committee member), Christopher Williams (committee member), Lawrence Marnett (committee member), Scott Hiebert (Committee Chair).
Subjects/Keywords: DNA replication; HDIs; small molecule
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APA ·
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Export
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Manager
APA (6th Edition):
Wells, C. E. (2013). Elucidating the mechanism of action of selective histone deacetylase inhibitors in cancer. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10934
Chicago Manual of Style (16th Edition):
Wells, Christina Elizabeth. “Elucidating the mechanism of action of selective histone deacetylase inhibitors in cancer.” 2013. Doctoral Dissertation, Vanderbilt University. Accessed March 02, 2021.
http://hdl.handle.net/1803/10934.
MLA Handbook (7th Edition):
Wells, Christina Elizabeth. “Elucidating the mechanism of action of selective histone deacetylase inhibitors in cancer.” 2013. Web. 02 Mar 2021.
Vancouver:
Wells CE. Elucidating the mechanism of action of selective histone deacetylase inhibitors in cancer. [Internet] [Doctoral dissertation]. Vanderbilt University; 2013. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/1803/10934.
Council of Science Editors:
Wells CE. Elucidating the mechanism of action of selective histone deacetylase inhibitors in cancer. [Doctoral Dissertation]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/10934
University of Aberdeen
29.
Christopher, Andrea.
Mathematical model of 'on-demand' histone protein synthesis during S phase in humans.
Degree: PhD, 2016, University of Aberdeen
URL: https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152477560005941
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.698846
► During DNA replication the DNA has to be unpacked, duplicated and repacked into chromatin, which is comprised of DNA and histone proteins (Nicholson and Muller,…
(more)
▼ During DNA replication the DNA has to be unpacked, duplicated and repacked into chromatin, which is comprised of DNA and histone proteins (Nicholson and Muller, 2008b). The coordinated replication of DNA and histone protein synthesis is vital for the correct chromatin formation (Marzluff et al., 2008). The mechanism controlling the histone gene expression is only partially understood, especially the mechanism controlling any disturbances in the coordination of DNA replication and histone protein synthesis. Previous experiments suggested that the regulation mechanism of histone balance could involve regulation by a free histone protein pool (Takami and Nakayama, 1997b; Takami and Nakayama, 1997a; Dominski et al., 2005; Kroeger et al., 1995). A mathematical model was produced by Dr Hameister (Hameister, 2012) to describe the control of histone production during S phase. The parameters used were taken from literature. Modifications were made using experimentally measured data to replace literature values (Harris et al., 1991; Clark, 2006; Strachen and Read, 2003). The aim of the project was to both optimise the model by defining parameters to reflect what occurs naturally in the cell, as well as trying to validate the model. The DNA replication rate was measured by FACS analysis and was input into the model. Histone RNA levels during S phase were measured by Northern blots and histone RNA degradation rates were analysed. To confirm that the modified DNA replication rate was producing accurate simulations, the curve produced for the mRNA levels could be compared to the experimentally measured mRNA values (Figure 4.3.1). The over expression of an H2B gene was verified using Western and Northern analysis. The validation of the model that the histone gene balance was being regulated by a free histone pool was not absolutely confirmed. However, results seen in Figure 3.6.1, showed an increase in H2B RNA degradation in the sample with the additional gene due to the additional histone proteins. Further work is required for confirmation of the regulation mechanism.
Subjects/Keywords: 572.8; DNA replication; Histones
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APA (6th Edition):
Christopher, A. (2016). Mathematical model of 'on-demand' histone protein synthesis during S phase in humans. (Doctoral Dissertation). University of Aberdeen. Retrieved from https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152477560005941 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.698846
Chicago Manual of Style (16th Edition):
Christopher, Andrea. “Mathematical model of 'on-demand' histone protein synthesis during S phase in humans.” 2016. Doctoral Dissertation, University of Aberdeen. Accessed March 02, 2021.
https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152477560005941 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.698846.
MLA Handbook (7th Edition):
Christopher, Andrea. “Mathematical model of 'on-demand' histone protein synthesis during S phase in humans.” 2016. Web. 02 Mar 2021.
Vancouver:
Christopher A. Mathematical model of 'on-demand' histone protein synthesis during S phase in humans. [Internet] [Doctoral dissertation]. University of Aberdeen; 2016. [cited 2021 Mar 02].
Available from: https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152477560005941 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.698846.
Council of Science Editors:
Christopher A. Mathematical model of 'on-demand' histone protein synthesis during S phase in humans. [Doctoral Dissertation]. University of Aberdeen; 2016. Available from: https://abdn.alma.exlibrisgroup.com/view/delivery/44ABE_INST/12152477560005941 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.698846
Northeastern University
30.
Silva, Michelle Cristine.
DNA replication by Escherichia coli DNA polymerase III is regulated by the umuD gene products.
Degree: PhD, Department of Chemistry, 2013, Northeastern University
URL: http://hdl.handle.net/2047/d20003301
► DNA polymerase III (DNA pol III) efficiently replicates the Escherichia coli genome, but it cannot bypass DNA damage. Instead, translesion synthesis (TLS) DNA polymerases are…
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▼ DNA polymerase III (DNA pol III) efficiently replicates the Escherichia coli genome, but it cannot bypass DNA damage. Instead, translesion synthesis (TLS) DNA polymerases are employed to replicate past damaged DNA; however, the exchange of replicative for TLS polymerases is not understood. The umuD gene products, which are up-regulated during the SOS response, were previously shown to bind to the alpha, beta, and epsilion subunits of DNA pol III. Full-length UmuD inhibits DNA replication and prevents mutagenic TLS, while the cleaved form UmuD' facilitates mutagenesis. In this work, we investigate the interactions between the alpha subunit of DNA pol III, the single-stranded DNA binding protein SSB, and UmuD and we find that these interactions regulate DNA replication in E. coli.; We show that the alpha subunit possesses two UmuD binding sites: at the N-terminus (residues 1-280) and the C-terminal domain (residues 956-975) of alpha. The C-terminal site favors UmuD over UmuD'. We also find that UmuD, but not UmuD', disrupts the alpha/beta complex. The C-terminal binding site is also adjacent to the single-stranded DNA (ssDNA) binding site of alpha. We have used single molecule DNA stretching experiments to demonstrate that UmuD specifically inhibits binding of alpha to ssDNA. We predict using molecular modeling that UmuD residue D91 is involved in the interaction between UmuD and alpha, and demonstrate that mutation of these residues decreases the affinity of alpha for UmuD. We propose that the interaction between alpha and UmuD contributes to the transition between replicative and TLS polymerases by removing alpha from the beta clamp and from ssDNA.; E. coli SSB binds to and protects ssDNA present during various DNA processing mechanisms such as DNA repair, recombination, and replication. Here, we investigate the role of SSB during DNA replication by DNA pol III. It has been previously shown that when SSB is bound to ssDNA at the replication fork, replication by the polymerase core, which consists of the alpha, epsilion, and theta subunits, is inhibited. In order for replication to occur in the presence of SSB the chi and psi subunits of DNA polymerase III are required. To date, the mechanism of this inhibition is poorly understood. We demonstrate that SSB inhibits DNA polymerase III by directly binding to the C-terminal domain of the alpha polymerase subunit. Interestingly, instead of binding the disordered tail of SSB like other proteins including the chi subunit, the alpha subunit binds the globular N-terminal domain of SSB that is responsible for binding ssDNA. Using single molecule force spectroscopy, we also show that the alpha subunit stabilizes the SSB/ssDNA interaction. In the absence of the alpha subunit, SSB stabilizes ssDNA below 20 pN and fully dissociates above 20 pN. However, in the presence of the alpha subunit, SSB does not dissociate above 20 pN and the energy required to dissociate SSB from ssDNA is increased by a factor of two. We show here that SSB inhibits replication by alpha both through direct…
Subjects/Keywords: DNA damage; DNA replication; Translesion Synthesis; Chemistry
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
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APA (6th Edition):
Silva, M. C. (2013). DNA replication by Escherichia coli DNA polymerase III is regulated by the umuD gene products. (Doctoral Dissertation). Northeastern University. Retrieved from http://hdl.handle.net/2047/d20003301
Chicago Manual of Style (16th Edition):
Silva, Michelle Cristine. “DNA replication by Escherichia coli DNA polymerase III is regulated by the umuD gene products.” 2013. Doctoral Dissertation, Northeastern University. Accessed March 02, 2021.
http://hdl.handle.net/2047/d20003301.
MLA Handbook (7th Edition):
Silva, Michelle Cristine. “DNA replication by Escherichia coli DNA polymerase III is regulated by the umuD gene products.” 2013. Web. 02 Mar 2021.
Vancouver:
Silva MC. DNA replication by Escherichia coli DNA polymerase III is regulated by the umuD gene products. [Internet] [Doctoral dissertation]. Northeastern University; 2013. [cited 2021 Mar 02].
Available from: http://hdl.handle.net/2047/d20003301.
Council of Science Editors:
Silva MC. DNA replication by Escherichia coli DNA polymerase III is regulated by the umuD gene products. [Doctoral Dissertation]. Northeastern University; 2013. Available from: http://hdl.handle.net/2047/d20003301
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