subject:(polymerase gamma)

University of Texas – Austin

1. Ziehr, Jessica Lea. Kinetics and specificity of human mitochondrial DNA polymerase gamma and HIV-1 reverse transcriptase.

Degree: PhD, Cell and Molecular Biology, 2014, University of Texas – Austin

URL: http://hdl.handle.net/2152/31296

► The human mitochondrial DNA (mtDNA) genome must be faithfully maintained by the mitochondrial DNA replication machinery. Deficiencies in mtDNA maintenance result in the accumulation of… (more)

▼ The human mitochondrial DNA (mtDNA) genome must be faithfully maintained by the mitochondrial DNA replication machinery. Deficiencies in mtDNA maintenance result in the accumulation of mutations and deletions, which have been associated with a number of neuromuscular degenerative disorders including, mtDNA depletion syndrome, Alpers syndrome, progressive external opthalmoplegia (PEO), and sensory ataxic neuropathy, dysarthria, and opthalmoparesis (SANDO). The mtDNA replication machinery is comprised of a nuclearly-encoded DNA polymerase gamma (Pol γ), single-stranded DNA binding protein (mtSSB), and a hexameric mtDNA helicase. In this work, we employed quantitative pre-steady state kinetic techniques to establish the mechanisms responsible for the replication of the human mitochondrial DNA by Pol γ and explored the effects of point mutations that are observed in heritable diseases. With our biochemical characterization of mutants of Pol γ, we have shown unique characteristics that would lead to profound physiological consequences over time. Additionally, we have made significant progress towards reconstitution of the mitochondrial DNA replisome by monitoring DNA polymerization that is dependent on helicase unwinding of double stranded DNA. Overall, this work provides a better understanding of the mechanism of mtDNA replication and has important implications toward understanding the role of mitochondrial DNA replication in mitochondrial disease, ageing and cancer. In addition to the work on the mtDNA replisome, we have applied pre-steady state kinetic techniques to better understand the mechanism of RNA-dependent DNA polymerization by HIV reverse transcriptase (HIV-RT). This enzyme is responsible for the replication of the viral genome in HIV and is a common target for anti-HIV drugs. We have characterized the role of enzyme conformational changes in the kinetics of incorporation of correct nucleotide and the Nucleotide Reverse Transcriptase Inhibitor (NRTI) AZT by wild-type enzyme, as well as a mutant with clinical resistance to AZT. This work provides a better understanding of the complete mechanism of RNA-dependent DNA polymerization, the changes in the mechanism in the presence of inhibitor and the development of resistance to this nucleoside analog; and thereby this work contributes to the long-term goal of designing more effective drugs that can possibly deter resistance and be used successfully for treatment of HIV. Advisors/Committee Members: Johnson, Kenneth A. (Kenneth Allen) (advisor), Lambowitz, Alan M (committee member), Russell, Rick (committee member), Marcotte, Edward M (committee member), Dalby, Kevin (committee member).

Subjects/Keywords: DNA polymerase; Pre-steady state kinetics; HIV reverse transcriptase; Polymerase gamma

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APA (6^th Edition):

Ziehr, J. L. (2014). Kinetics and specificity of human mitochondrial DNA polymerase gamma and HIV-1 reverse transcriptase. (Doctoral Dissertation). University of Texas – Austin. Retrieved from http://hdl.handle.net/2152/31296

Chicago Manual of Style (16^th Edition):

Ziehr, Jessica Lea. “Kinetics and specificity of human mitochondrial DNA polymerase gamma and HIV-1 reverse transcriptase.” 2014. Doctoral Dissertation, University of Texas – Austin. Accessed January 22, 2021. http://hdl.handle.net/2152/31296.

MLA Handbook (7^th Edition):

Ziehr, Jessica Lea. “Kinetics and specificity of human mitochondrial DNA polymerase gamma and HIV-1 reverse transcriptase.” 2014. Web. 22 Jan 2021.

Vancouver:

Ziehr JL. Kinetics and specificity of human mitochondrial DNA polymerase gamma and HIV-1 reverse transcriptase. [Internet] [Doctoral dissertation]. University of Texas – Austin; 2014. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/2152/31296.

Council of Science Editors:

Ziehr JL. Kinetics and specificity of human mitochondrial DNA polymerase gamma and HIV-1 reverse transcriptase. [Doctoral Dissertation]. University of Texas – Austin; 2014. Available from: http://hdl.handle.net/2152/31296

2. Meng, Qingchao, master of arts in cell and molecular biology. Approaching the crystal structure of the polymerase γ catalytic complex: Approaching the crystal structure of the polymerase [gamma] catalytic complex.

Degree: MA, Cell and Molecular Biology, 2011, University of Texas – Austin

URL: http://hdl.handle.net/2152/ETD-UT-2011-08-4330

► In this thesis, a 4.7Å crystal structure of the human mitochondria DNA polymerase γ catalytic complex is reported. Though the DNA substrate-binding site is not… (more)

Subjects/Keywords: Pol γ; Crystal structure; Catalytic complex; Polymerase γ; Pol gamma; Polymerase gamma; Human mitochondria DNA polymerase gamma; DNA; DNA binding site; Human mitochondria DNA polymerase γ

…polymerase and exonuclease domains of the catalytic subunit of the Pol γ-DNA complex (red)… …nucleoside inhibitors of mitochondrial DNA polymerase gamma." Methods 51(4): 392-8… …laevis mitochondrial DNA polymerase gamma increases processivity of the catalytic subunit of… …human DNA polymerase gamma and is related to class II aminoacyl-tRNA synthetases." Mol… …heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma."…

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APA (6^th Edition):

Meng, Qingchao, m. o. a. i. c. a. m. b. (2011). Approaching the crystal structure of the polymerase γ catalytic complex: Approaching the crystal structure of the polymerase [gamma] catalytic complex. (Masters Thesis). University of Texas – Austin. Retrieved from http://hdl.handle.net/2152/ETD-UT-2011-08-4330

Chicago Manual of Style (16^th Edition):

Meng, Qingchao, master of arts in cell and molecular biology. “Approaching the crystal structure of the polymerase γ catalytic complex: Approaching the crystal structure of the polymerase [gamma] catalytic complex.” 2011. Masters Thesis, University of Texas – Austin. Accessed January 22, 2021. http://hdl.handle.net/2152/ETD-UT-2011-08-4330.

MLA Handbook (7^th Edition):

Meng, Qingchao, master of arts in cell and molecular biology. “Approaching the crystal structure of the polymerase γ catalytic complex: Approaching the crystal structure of the polymerase [gamma] catalytic complex.” 2011. Web. 22 Jan 2021.

Vancouver:

Meng, Qingchao moaicamb. Approaching the crystal structure of the polymerase γ catalytic complex: Approaching the crystal structure of the polymerase [gamma] catalytic complex. [Internet] [Masters thesis]. University of Texas – Austin; 2011. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/2152/ETD-UT-2011-08-4330.

Council of Science Editors:

Meng, Qingchao moaicamb. Approaching the crystal structure of the polymerase γ catalytic complex: Approaching the crystal structure of the polymerase [gamma] catalytic complex. [Masters Thesis]. University of Texas – Austin; 2011. Available from: http://hdl.handle.net/2152/ETD-UT-2011-08-4330

Brigham Young University

3. Brammer, Jeffrey M. Organellar DNA Polymerases Gamma I and II in Arabidopsis thaliana.

Degree: MS, 2010, Brigham Young University

URL: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=3533&context=etd

► Plants have two organelles outside the nucleus which carry their own DNA, mitochondria and chloroplasts. These organelles are descendants of bacteria that were engulfed… (more)

▼ Plants have two organelles outside the nucleus which carry their own DNA, mitochondria and chloroplasts. These organelles are descendants of bacteria that were engulfed by their host according to the endosymbiotic theory. Over time, DNA has been exchanged between these organelles and the nucleus. Two polymerases, DNA Polymerases Gamma I and II, are encoded in the nucleus and remain under nuclear control, but are transported into the mitochondria and chloroplasts. DNA polymerases gamma I and II are two organelle polymerases which have been studied through sequence analysis and shown to localize to both mitochondria and chloroplasts. Little has been done to characterize the activities of these polymerases. Work in tobacco showed the homology of these polymerases to each other and to DNA Polymerase I in bacteria. They have been characterized as being part of the DNA Polymerase A family of polymerases. In my research I have studied the effect of T-DNA insertions within the DNA Polymerase Gamma I and II genes. Since these DNA Polymerases are targeted to the mitochondria and chloroplasts, I studied the effect of knocking out these genes. A plant heterozygous for an insert in DNA Polymerase Gamma I grows slightly slower than wild type plants with an approximately 20% reduction in mitochondrial and chloroplast DNA copy number. A plant homozygous for an insert in this same gene has a drastic phenotype with stunted plants that grow to around 1 inch tall, with floral stems, and have an approximately 50-55% reduction in mitochondrial and chloroplast DNA copy number. Wild type plants can grow to a height of 12-18 inches with floral stems as a comparison. A plant heterozygous for an insert in the DNA Polymerase Gamma II gene grows slightly slower than wild type plants and has an approximately 15% reduction in mitochondrial DNA copy number and a 50% reduction in chloroplast DNA copy number. These plants also produce much less seed than do other mutants and wild type plants.

Subjects/Keywords: DNA polymerase; Arabidopsis; Arabidopsis thaliana; gamma polymerase; mitochondrion; mitochondria; chloroplast; plastid; DNA replication; Microbiology

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APA (6^th Edition):

Brammer, J. M. (2010). Organellar DNA Polymerases Gamma I and II in Arabidopsis thaliana. (Masters Thesis). Brigham Young University. Retrieved from https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=3533&context=etd

Chicago Manual of Style (16^th Edition):

Brammer, Jeffrey M. “Organellar DNA Polymerases Gamma I and II in Arabidopsis thaliana.” 2010. Masters Thesis, Brigham Young University. Accessed January 22, 2021. https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=3533&context=etd.

MLA Handbook (7^th Edition):

Brammer, Jeffrey M. “Organellar DNA Polymerases Gamma I and II in Arabidopsis thaliana.” 2010. Web. 22 Jan 2021.

Vancouver:

Brammer JM. Organellar DNA Polymerases Gamma I and II in Arabidopsis thaliana. [Internet] [Masters thesis]. Brigham Young University; 2010. [cited 2021 Jan 22]. Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=3533&context=etd.

Council of Science Editors:

Brammer JM. Organellar DNA Polymerases Gamma I and II in Arabidopsis thaliana. [Masters Thesis]. Brigham Young University; 2010. Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=3533&context=etd

Tampere University

4. Nurminen, Anssi. A Bioinformatics Approach to Analyzing the Pathogenicity of Mutations by Using Protein Structure Information : A Study on DNA Polymerase Gamma .

Degree: 2018, Tampere University

URL: https://trepo.tuni.fi/handle/10024/102657

► Geneettisen testauksen kustannusten laskiessa, pullonkaulaksi saatavilla olevan tiedon hyödyntämiseen on muodostumassa tietämyksemme eri geneettisten variaatioiden ja mutaatioden merkityksestä. Jokaisella henkilöllä on satoja, yksilöllisiä variaatioita perimässään… (more)

▼ Geneettisen testauksen kustannusten laskiessa, pullonkaulaksi saatavilla olevan tiedon hyödyntämiseen on muodostumassa tietämyksemme eri geneettisten variaatioiden ja mutaatioden merkityksestä. Jokaisella henkilöllä on satoja, yksilöllisiä variaatioita perimässään joiden vaikutuksia ei tunneta. Tilanteissa joissa perinöllisen sairauden syytä pyritään selvittämään geenitutkimuksen avulla nämä variaatiot pitää pystyä tunnistamaan joko merkityksettömiksi tai merkitysellisiksi taudin kannalta, jotta oikean diagnoosin tekeminen ja sopivien hoitometelmien valinta on mahdollista. Rakennebiologia ja bioinformatiikka tarjoavat monia keinoja mutaatioiden vaikutusten tarkasteluun. Tässä tutkimuksessa käytetään esimerkkinä DNA polymeraasi gammaa (Pol γ), joka on ainoa tunnettu entsyymi joka replikoi ja ylläpitää mitokondrionaalista DNA:ta. Pol γ tarjoaa uniikin tutkimuskohteen pistemutaatioiden vaikutuksille sen kriittisen toiminnalisuuden ja korvaavien mekanismien puuttumisen vuoksi. Pol γ:n tunnetun proteiinirakenteen, yli 700 hengen potilasaineiston ja mutaatioiden biokemiallisen karakterisoinnin avulla pystymme tuottamaan ennennäkemättömän tarkan kuvan mutaatioiden vaikutusmekanismeista ja ennustamaan sekä tunnettujen, että vielä tuntemattomien mutaatioiden vaikutusta taudin puhkeamiseen ja etenemiseen. Tämän tutkimuksen osana olemme kehittäneet uuden algoritmin proteiinien kolmiulotteisten rakenteiden tutkimukseen ja analysointiin, nimeltään StructureMapper. StructureMapper on skaalautuva, suurien aineistojen analysoitiin suunniteltu algoritmi, joka tarjoaa mahdollisuuksia analysoida esimerkikisi ennustusalgoritmien tulosten luotettavuutta, kokeellisen datan laatua, ja sitä voidaan hyödyntää myös mutaatioiden haitallisuuden ennustamisessa ja tutkimuksessa. Kaikkia tämän tutkimuksen osana tuotetuista menetelmistä ja työkaluista voidaan hyödyntää yleiskäyttöisesti proteiinien tutkimuksessa.; Genetic testing is becoming more and more prevalent in the field of medicine. The bottleneck in making a diagnosis based on genetic information has shifted from being able to acquire the required information by sequencing the genome of a patient, to understanding the effects of the detected, unique variations in the DNA. Mutations in the DNA can affect proteins and their structure on many levels. In a clinical setting, being able to separate the benign mutations from the pathogenic is of utmost importance. DNA polymerase gamma (Pol γ) offers an intriguing study subject in the world of structural biology. It is the sole enzyme responsible for replicating mitochondrial DNA. Defects in its functionality can manifest with a wide variety of symptoms that are often due to single point mutations that affect its structure in a deleterious way. Through analysis of the structure of Pol γ, combined with over 700 available patient case reports and biochemical characterization of some of the mutations, we have gained an unprecedented view to the reasons behind the mutations that lead to pathogenicity and altered biological functionality of…

Subjects/Keywords: DNA polymeraasi gamma ; POLG ; mutaatio ; proteiinirakenne ; patogeenisyys ; DNA polymerase gamma ; mutation ; protein structure ; pathogenicity

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APA (6^th Edition):

Nurminen, A. (2018). A Bioinformatics Approach to Analyzing the Pathogenicity of Mutations by Using Protein Structure Information : A Study on DNA Polymerase Gamma . (Doctoral Dissertation). Tampere University. Retrieved from https://trepo.tuni.fi/handle/10024/102657

Chicago Manual of Style (16^th Edition):

Nurminen, Anssi. “A Bioinformatics Approach to Analyzing the Pathogenicity of Mutations by Using Protein Structure Information : A Study on DNA Polymerase Gamma .” 2018. Doctoral Dissertation, Tampere University. Accessed January 22, 2021. https://trepo.tuni.fi/handle/10024/102657.

MLA Handbook (7^th Edition):

Nurminen, Anssi. “A Bioinformatics Approach to Analyzing the Pathogenicity of Mutations by Using Protein Structure Information : A Study on DNA Polymerase Gamma .” 2018. Web. 22 Jan 2021.

Vancouver:

Nurminen A. A Bioinformatics Approach to Analyzing the Pathogenicity of Mutations by Using Protein Structure Information : A Study on DNA Polymerase Gamma . [Internet] [Doctoral dissertation]. Tampere University; 2018. [cited 2021 Jan 22]. Available from: https://trepo.tuni.fi/handle/10024/102657.

Council of Science Editors:

Nurminen A. A Bioinformatics Approach to Analyzing the Pathogenicity of Mutations by Using Protein Structure Information : A Study on DNA Polymerase Gamma . [Doctoral Dissertation]. Tampere University; 2018. Available from: https://trepo.tuni.fi/handle/10024/102657

Vanderbilt University

5. Song, Zhuo. Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data.

Degree: PhD, Human Genetics, 2012, Vanderbilt University

URL: http://hdl.handle.net/1803/10702

► The activity of polymerase ã (pol ã) is complicated. To understand how its kinetics values affect the final function of the pol ã, I created… (more)

Subjects/Keywords: tumor somatic mutations; targeted sequencing; NRTI; polymerase gamma; mtDNA replication

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APA (6^th Edition):

Song, Z. (2012). Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10702

Chicago Manual of Style (16^th Edition):

Song, Zhuo. “Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed January 22, 2021. http://hdl.handle.net/1803/10702.

MLA Handbook (7^th Edition):

Song, Zhuo. “Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data.” 2012. Web. 22 Jan 2021.

Vancouver:

Song Z. Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/1803/10702.

Council of Science Editors:

Song Z. Stochastic modeling of mitochondrial polymerase gamma replication and novel algorithms to enrich rare disease alleles and detect tumor somatic mutations in deep sequencing data. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/10702

Brigham Young University

6. Cupp, John D. Characterization of the Cellular and Organellar Dynamics that Occur with a Partial Depletion of Mitochondrial DNA when Arabidopsis Organellar DNA Polymerase IB is Mutated.

Degree: PhD, 2012, Brigham Young University

URL: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4746&context=etd

► Plant mitochondrial genomes are large and complex, and the mechanisms for maintaining mitochondrial DNA (mtDNA) remain unclear. Arabidopsis thaliana has two DNA polymerase genes, polIA… (more)

Subjects/Keywords: polymerase gamma; PolIA; PolIB; TWINKLE; mitochondria; DNA replication; Microbiology

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APA (6^th Edition):

Cupp, J. D. (2012). Characterization of the Cellular and Organellar Dynamics that Occur with a Partial Depletion of Mitochondrial DNA when Arabidopsis Organellar DNA Polymerase IB is Mutated. (Doctoral Dissertation). Brigham Young University. Retrieved from https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4746&context=etd

Chicago Manual of Style (16^th Edition):

Cupp, John D. “Characterization of the Cellular and Organellar Dynamics that Occur with a Partial Depletion of Mitochondrial DNA when Arabidopsis Organellar DNA Polymerase IB is Mutated.” 2012. Doctoral Dissertation, Brigham Young University. Accessed January 22, 2021. https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4746&context=etd.

MLA Handbook (7^th Edition):

Cupp, John D. “Characterization of the Cellular and Organellar Dynamics that Occur with a Partial Depletion of Mitochondrial DNA when Arabidopsis Organellar DNA Polymerase IB is Mutated.” 2012. Web. 22 Jan 2021.

Vancouver:

Cupp JD. Characterization of the Cellular and Organellar Dynamics that Occur with a Partial Depletion of Mitochondrial DNA when Arabidopsis Organellar DNA Polymerase IB is Mutated. [Internet] [Doctoral dissertation]. Brigham Young University; 2012. [cited 2021 Jan 22]. Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4746&context=etd.

Council of Science Editors:

Cupp JD. Characterization of the Cellular and Organellar Dynamics that Occur with a Partial Depletion of Mitochondrial DNA when Arabidopsis Organellar DNA Polymerase IB is Mutated. [Doctoral Dissertation]. Brigham Young University; 2012. Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4746&context=etd

Université Catholique de Louvain

7. Szczepanowska, Karolina. A cluster of pathogenic mutations in the 3'-5' exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation.

Degree: 2011, Université Catholique de Louvain

URL: http://hdl.handle.net/2078.1/73438

►

DNA polymerase gamma (pol g in human, Mip1 in yeast) is the unique DNA replicase found in mitochondria. Pol g plays a key role in… (more)

Subjects/Keywords: Mitochondrial DNA polymerase gamma; Mitochondrial disorders; Mutations; Yeast

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APA (6^th Edition):

Szczepanowska, K. (2011). A cluster of pathogenic mutations in the 3'-5' exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation. (Thesis). Université Catholique de Louvain. Retrieved from http://hdl.handle.net/2078.1/73438

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Szczepanowska, Karolina. “A cluster of pathogenic mutations in the 3'-5' exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation.” 2011. Thesis, Université Catholique de Louvain. Accessed January 22, 2021. http://hdl.handle.net/2078.1/73438.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Szczepanowska, Karolina. “A cluster of pathogenic mutations in the 3'-5' exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation.” 2011. Web. 22 Jan 2021.

Vancouver:

Szczepanowska K. A cluster of pathogenic mutations in the 3'-5' exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation. [Internet] [Thesis]. Université Catholique de Louvain; 2011. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/2078.1/73438.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Szczepanowska K. A cluster of pathogenic mutations in the 3'-5' exonuclease domain of DNA polymerase gamma defines a novel module coupling DNA synthesis and degradation. [Thesis]. Université Catholique de Louvain; 2011. Available from: http://hdl.handle.net/2078.1/73438

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Texas – Austin

8. Estep, Patricia Ann. The role of residue Y955 of mitochondrial DNA polymerase [gamma] in nucleotide binding and discrimination.

Degree: MA, Biochemistry, 2010, University of Texas – Austin

URL: http://hdl.handle.net/2152/ETD-UT-2010-12-2395

► The human mitochondrial polymerase (pol γ) is a nuclearly-encoded polymerase that is solely responsible for the faithful replication and repair of the mitochondrial genome. The… (more)

Subjects/Keywords: Pre-steady state kinetics; DNA polymerase gamma

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APA (6^th Edition):

Estep, P. A. (2010). The role of residue Y955 of mitochondrial DNA polymerase [gamma] in nucleotide binding and discrimination. (Masters Thesis). University of Texas – Austin. Retrieved from http://hdl.handle.net/2152/ETD-UT-2010-12-2395

Chicago Manual of Style (16^th Edition):

Estep, Patricia Ann. “The role of residue Y955 of mitochondrial DNA polymerase [gamma] in nucleotide binding and discrimination.” 2010. Masters Thesis, University of Texas – Austin. Accessed January 22, 2021. http://hdl.handle.net/2152/ETD-UT-2010-12-2395.

MLA Handbook (7^th Edition):

Estep, Patricia Ann. “The role of residue Y955 of mitochondrial DNA polymerase [gamma] in nucleotide binding and discrimination.” 2010. Web. 22 Jan 2021.

Vancouver:

Estep PA. The role of residue Y955 of mitochondrial DNA polymerase [gamma] in nucleotide binding and discrimination. [Internet] [Masters thesis]. University of Texas – Austin; 2010. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/2152/ETD-UT-2010-12-2395.

Council of Science Editors:

Estep PA. The role of residue Y955 of mitochondrial DNA polymerase [gamma] in nucleotide binding and discrimination. [Masters Thesis]. University of Texas – Austin; 2010. Available from: http://hdl.handle.net/2152/ETD-UT-2010-12-2395

9. Xia, Yang. The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6.

Degree: PhD, 2011, University of Cambridge

URL: http://www.dspace.cam.ac.uk/handle/1810/240633https://www.repository.cam.ac.uk/bitstream/1810/240633/2/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/5/final.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/6/final.pdf.jpg

► Type I PIP kinases (phosphatidylinositol 4-phosphate 5-kinases, PIP5Ks) catalyse the majority of cellular synthesis of PI(4,5)P2. To date, three mammalian isoforms (r1, r2, r3) have… (more)

▼ Type I PIP kinases (phosphatidylinositol 4-phosphate 5-kinases, PIP5Ks) catalyse the majority of cellular synthesis of PI(4,5)P2. To date, three mammalian isoforms (r1, r2, r3) have been found. PIP5KIr is subject to complex C-terminal splice variation, enhancing its transcriptional diversity through evolution and producing at least 5 known spliceoforms in the mammals. This study addresses several important questions. (1) Several remarkable differences have been discovered between the neuronal splice variant PIP5KIr_i3 and its close variant, Ir_i2, whose peptide lacks a 26-AA insert near its C-terminus. This study attempts to map these behavioural differences onto motifs within the peptide insert. Furthermore, a site of point mutation is identified near the activation loop, which amplifies the above differences. (2) This study documents properties of the more recently discovered PIP5KIr_i3, about which relatively little is known, for example, the regulation of its subcellular localisation, kinase activity and post-translational modifications. By site-directed mutagenesis and examining more closely several crucial motifs, insight is gained into the putative relationship between the enzyme’s phosphorylation state, cellular localisation, lipid kinase activity and autophosphorylation. (3) The discovery of a new PIP5KIr splice variant, Ir_v6, is described. First discovered in rodents, PIP5KIr_i6 encompasses the 26-AA insert of Ir_i3, but lacks the common C-terminus of Ir_i2 and Ir_i3 which contains peptide motifs that have several roles in vivo. A polyclonal antibody against the C-terminus of Ir_i6 was also developed. Preliminary characterisation of Ir_i6 demonstrates a similar subcellular localisation, but a wider expression profile than its close relative, Ir_i3, suggesting potentially differential functions across tissues and at various developmental stages. (4) The existence of Ir_v3 and Ir_v6 is also confirmed in humans. In light of recent findings of other novel human spliceoforms, this is shown to be a case of intra-exonic splicing producing “alternative 5’ splice site” exons in the human. Overall, this thesis should help to better understand the regulation and physiological roles of PIP5KIr and, specifically, its different splice variants.

Subjects/Keywords: Phosphatidylinositol 4-phosphate 5-kinase I gamma; Type I PIP5K; Phosphorylation; Alternative splicing; Discovery; Subcellular localisation; Confocal microscopy; Polymerase chain reaction; Kinase assay; Autophosphorylation

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APA (6^th Edition):

Xia, Y. (2011). The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6. (Doctoral Dissertation). University of Cambridge. Retrieved from http://www.dspace.cam.ac.uk/handle/1810/240633https://www.repository.cam.ac.uk/bitstream/1810/240633/2/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/5/final.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/6/final.pdf.jpg

Chicago Manual of Style (16^th Edition):

Xia, Yang. “The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6.” 2011. Doctoral Dissertation, University of Cambridge. Accessed January 22, 2021. http://www.dspace.cam.ac.uk/handle/1810/240633https://www.repository.cam.ac.uk/bitstream/1810/240633/2/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/5/final.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/6/final.pdf.jpg.

MLA Handbook (7^th Edition):

Xia, Yang. “The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6.” 2011. Web. 22 Jan 2021.

Vancouver:

Xia Y. The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6. [Internet] [Doctoral dissertation]. University of Cambridge; 2011. [cited 2021 Jan 22]. Available from: http://www.dspace.cam.ac.uk/handle/1810/240633https://www.repository.cam.ac.uk/bitstream/1810/240633/2/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/5/final.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/6/final.pdf.jpg.

Council of Science Editors:

Xia Y. The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6. [Doctoral Dissertation]. University of Cambridge; 2011. Available from: http://www.dspace.cam.ac.uk/handle/1810/240633https://www.repository.cam.ac.uk/bitstream/1810/240633/2/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/5/final.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/240633/6/final.pdf.jpg

University of Cambridge

10. Xia, Yang. The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6.

Degree: PhD, 2011, University of Cambridge

URL: https://doi.org/10.17863/CAM.15898 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555206

► Type I PIP kinases (phosphatidylinositol 4-phosphate 5-kinases, PIP5Ks) catalyse the majority of cellular synthesis of PI(4,5)P2. To date, three mammalian isoforms (r1, r2, r3) have… (more)

▼ Type I PIP kinases (phosphatidylinositol 4-phosphate 5-kinases, PIP5Ks) catalyse the majority of cellular synthesis of PI(4,5)P2. To date, three mammalian isoforms (r1, r2, r3) have been found. PIP5KIr is subject to complex C-terminal splice variation, enhancing its transcriptional diversity through evolution and producing at least 5 known spliceoforms in the mammals. This study addresses several important questions. (1) Several remarkable differences have been discovered between the neuronal splice variant PIP5KIr_i3 and its close variant, Ir_i2, whose peptide lacks a 26-AA insert near its C-terminus. This study attempts to map these behavioural differences onto motifs within the peptide insert. Furthermore, a site of point mutation is identified near the activation loop, which amplifies the above differences. (2) This study documents properties of the more recently discovered PIP5KIr_i3, about which relatively little is known, for example, the regulation of its subcellular localisation, kinase activity and post-translational modifications. By site-directed mutagenesis and examining more closely several crucial motifs, insight is gained into the putative relationship between the enzyme’s phosphorylation state, cellular localisation, lipid kinase activity and autophosphorylation. (3) The discovery of a new PIP5KIr splice variant, Ir_v6, is described. First discovered in rodents, PIP5KIr_i6 encompasses the 26-AA insert of Ir_i3, but lacks the common C-terminus of Ir_i2 and Ir_i3 which contains peptide motifs that have several roles in vivo. A polyclonal antibody against the C-terminus of Ir_i6 was also developed. Preliminary characterisation of Ir_i6 demonstrates a similar subcellular localisation, but a wider expression profile than its close relative, Ir_i3, suggesting potentially differential functions across tissues and at various developmental stages. (4) The existence of Ir_v3 and Ir_v6 is also confirmed in humans. In light of recent findings of other novel human spliceoforms, this is shown to be a case of intra-exonic splicing producing “alternative 5’ splice site” exons in the human. Overall, this thesis should help to better understand the regulation and physiological roles of PIP5KIr and, specifically, its different splice variants.

Subjects/Keywords: 615.1; Phosphatidylinositol 4-phosphate 5-kinase I gamma; Type I PIP5K; Phosphorylation; Alternative splicing; Discovery; Subcellular localisation; Confocal microscopy; Polymerase chain reaction; Kinase assay; Autophosphorylation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Xia, Y. (2011). The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6. (Doctoral Dissertation). University of Cambridge. Retrieved from https://doi.org/10.17863/CAM.15898 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555206

Chicago Manual of Style (16^th Edition):

Xia, Yang. “The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6.” 2011. Doctoral Dissertation, University of Cambridge. Accessed January 22, 2021. https://doi.org/10.17863/CAM.15898 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555206.

MLA Handbook (7^th Edition):

Xia, Yang. “The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6.” 2011. Web. 22 Jan 2021.

Vancouver:

Xia Y. The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6. [Internet] [Doctoral dissertation]. University of Cambridge; 2011. [cited 2021 Jan 22]. Available from: https://doi.org/10.17863/CAM.15898 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555206.

Council of Science Editors:

Xia Y. The localisation and regulation of phosphatidylinositol-4-phosphate 5-Kinase gamma splice variants and the discovery of a new mammalian splice variant, PIP5KIγ_v6. [Doctoral Dissertation]. University of Cambridge; 2011. Available from: https://doi.org/10.17863/CAM.15898 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555206

11. Bakthavatchalu, Vasudevan. MnSOD AND AUTOPHAGY IN PREVENTION OF OXIDATIVE MITOCHONDRIAL INJURIES INDUCED BY UVB IN MURINE SKIN.

Degree: 2012, University of Kentucky

URL: https://uknowledge.uky.edu/toxicology_etds/2

► UVB radiation is a known environmental carcinogen that causes DNA damage and increase ROS generation in mitochondria. Accumulating evidence suggests that mtDNA damage and increased… (more)

▼ UVB radiation is a known environmental carcinogen that causes DNA damage and increase ROS generation in mitochondria. Accumulating evidence suggests that mtDNA damage and increased ROS generation trigger mitochondrial translocation of p53. Within mitochondria, p53 interacts with nucleoid macromolecular complexes such as mitochondrial antioxidant MnSOD, mitochondrial DNA polymerase Polγ, and mtDNA. Mitochondria are considered to be a potential source for damage-associated molecular patterns (DAMPs) such as mtDNA, cytochrome C, ATP, and formyl peptides. Intracytoplasmic release of DAMPs can trigger inflammasome formation and programmed cell death processes. Autophagic clearance of mitochondria with compromised integrity can inhibit inflammatory and cell death processes. In this study we investigated whether and how MnSOD plays a protective role in UVB-induced mitochondrial damage. The possibility of MnSOD participating in the mtDNA repair process was addressed in vivo using transgenic and pharmacological approaches. The results demonstrate that MnSOD functions as a fidelity protein that maintains the activity of Polγ by preventing UVB-induced nitration and inactivation of Polγ and that MnSOD coordinates with p53 to prevent mtDNA damage. We also investigated whether autophagy is an adaptive response mechanism by which skin cells respond to mitochondrial injury, using mouse keratinocytes (JB6 cells) and C57/BL6 mice as in vitro and in vivo models. The results demonstrate that UVB induces autophagy initiation in murine skin tissues and that down regulation of AKTmTOR levels triggers initiation of autophagy processes. These results suggest that autophagy may play a role in scavenging damaged mitochondria. Taken together, the results from these studies suggest that MnSOD plays a protective role against UVB-induced mitochondria injury beyond its known antioxidant function. Within the mitochondrial matrix, MnSOD acts as an antioxidant and fidelity protein by prevention of UVB-induced nitration of Polγ. The functions of MnSOD may be to enhance mitochondrial membrane integrity and to prevent the genesis of oxidatively damaged mitochondrial components and subsequent intracytoplasmic spillage. Activation of autophagy serves as an additional response that scavenges damaged mitochondria.

Subjects/Keywords: MnSOD; Polymerase gamma; Autophagy; UVB; Mitochondria; Medical Toxicology

…POLYMERASE GAMMA.................................................24 1.8 AUTOPHAGY… …Peroxynitrite PI3K Phosphoinositide 3-kinase Polγ Polymerase gamma ROS Reactive oxygen species… …recognized by XPC/HHR23B. In TCR, the lesion is recognized by RNA polymerase II (Petit and…

12 more images…

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APA (6^th Edition):

Bakthavatchalu, V. (2012). MnSOD AND AUTOPHAGY IN PREVENTION OF OXIDATIVE MITOCHONDRIAL INJURIES INDUCED BY UVB IN MURINE SKIN. (Doctoral Dissertation). University of Kentucky. Retrieved from https://uknowledge.uky.edu/toxicology_etds/2

Chicago Manual of Style (16^th Edition):

Bakthavatchalu, Vasudevan. “MnSOD AND AUTOPHAGY IN PREVENTION OF OXIDATIVE MITOCHONDRIAL INJURIES INDUCED BY UVB IN MURINE SKIN.” 2012. Doctoral Dissertation, University of Kentucky. Accessed January 22, 2021. https://uknowledge.uky.edu/toxicology_etds/2.

MLA Handbook (7^th Edition):

Bakthavatchalu, Vasudevan. “MnSOD AND AUTOPHAGY IN PREVENTION OF OXIDATIVE MITOCHONDRIAL INJURIES INDUCED BY UVB IN MURINE SKIN.” 2012. Web. 22 Jan 2021.

Vancouver:

Bakthavatchalu V. MnSOD AND AUTOPHAGY IN PREVENTION OF OXIDATIVE MITOCHONDRIAL INJURIES INDUCED BY UVB IN MURINE SKIN. [Internet] [Doctoral dissertation]. University of Kentucky; 2012. [cited 2021 Jan 22]. Available from: https://uknowledge.uky.edu/toxicology_etds/2.

Council of Science Editors:

Bakthavatchalu V. MnSOD AND AUTOPHAGY IN PREVENTION OF OXIDATIVE MITOCHONDRIAL INJURIES INDUCED BY UVB IN MURINE SKIN. [Doctoral Dissertation]. University of Kentucky; 2012. Available from: https://uknowledge.uky.edu/toxicology_etds/2

12. Aquino, Simone. Efeitos da radiação gama no crescimento de aspergillus flavus produtor de aflatoxinas e no emprego da técnica da reação em cadeia da polimerase (PCR) em amostras de grãos de milho inoculadas artificialmente.

Degree: Mestrado, Tecnologia Nuclear - Aplicações, 2004, University of São Paulo

URL: http://www.teses.usp.br/teses/disponiveis/85/85131/tde-16042012-105910/ ;

►

O presente trabalho teve como objetivos verificar os efeitos da radiação gama em grãos de milho contaminados artificialmente com Aspergillus flavus Link produtor de aflatoxinas;… (more)

▼

O presente trabalho teve como objetivos verificar os efeitos da radiação gama em grãos de milho contaminados artificialmente com Aspergillus flavus Link produtor de aflatoxinas; demonstrar a aplicação da técnica da Reação em Cadeia da Polimerase (PCR) no diagnóstico de A. flavus, bem como verificar o efeito da radiação no perfil das bandas de DNA. Vinte amostras de grãos de milho com 200 g cada foram irradiadas individualmente com 20 kGy, para eliminar a contaminação microbiana. Em seguida, as amostras foram inoculadas com A. flavus toxigênico (1 x 106 esporos / ml), incubadas por 15 dias a 25 °C em ambiente com umidade relativa ao redor de 97,5% e irradiadas com 0; 2; 5 e 10 kGy. As amostras, 5 para cada dose de irradiação, foram analisadas individualmente quanto ao número de células fúngicas, atividade de água, teste de viabilidade (diacetato de fluoresceína e brometo de etídio), PCR e detecção de aflatoxinas (AFB). Os resultados demonstraram que as doses utilizadas foram efetivas na redução do número de Unidades Formadoras de Colônias (UFC/g), principalmente as doses de 5 e 10 kGy. Em adição, o teste de viabilidade mostrou uma diminuição de células viáveis com o aumento das doses de irradiação. A redução de AFB1 e AFB2 foi mais eficiente com o emprego de 2 kGy, comparativamente à dose de 5 kGy, enquanto a dose de 10 kGy degradou totalmente as aflatoxinas. Além disso, observou-se que AFB2 apresentou-se mais radiosensível. O emprego da técnica de PCR revelou a presença de bandas de DNA em todas as amostras.

The aim of this present study was to verify the effects of gamma radiation on the growth of Aspergillus flavus Link aflatoxins producer; to demonstrate the application of Polymerase Chain Reaction (PCR) technique in the diagnostic of A. Flavus, as well to verify the effect of radiation in the profile of DNA bands. Twenty samples of grains maize with 200 g each were individually irradiated with 20 kGy, to eliminate the microbial contamination. In following, the samples were inoculated with an toxigenic A. flavus (1x106 spores/ml), incubated for 15 days at 25 °C with a relative humidity of around 97,5% and irradiated with 0; 2; 5 and 10 kGy. The samples, 5 to each dose of irradiation, were individually analyzed for the number of fungal cells, water activity, viability test (fluorescein diacetate and ethidium bromide), PCR and aflatoxins (AFB) detection. The results showed that the doses used were effectives in reducing the number of Colony Forming Units (CFU/g) mainly the doses of 5 and 10 kGy. In addition, the viability test showed a decrease of viable cells with increase of irradiation doses. The reduction of AFB1 and AFB2, was more efficient with the use of 2 kGy in comparison with the dose of 5 kGy, while the dose of 10 kGy, degraded the aflatoxins. Thereby, it was observed that AFB2 showed to be more radiosensitive. The use of PCR technique showed the presence of DNA bands, in all samples

Advisors/Committee Members: Villavicencio, Anna Lucia Casañas Haasis.

Subjects/Keywords: aflatoxinas; aflatoxins; Aspergillus; Aspergillus; biological radiation effects; DNA; DNA; gamma radiation; maize; polymerase chain reaction; radiação gama; seeds

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Aquino, S. (2004). Efeitos da radiação gama no crescimento de aspergillus flavus produtor de aflatoxinas e no emprego da técnica da reação em cadeia da polimerase (PCR) em amostras de grãos de milho inoculadas artificialmente. (Masters Thesis). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/85/85131/tde-16042012-105910/ ;

Chicago Manual of Style (16^th Edition):

Aquino, Simone. “Efeitos da radiação gama no crescimento de aspergillus flavus produtor de aflatoxinas e no emprego da técnica da reação em cadeia da polimerase (PCR) em amostras de grãos de milho inoculadas artificialmente.” 2004. Masters Thesis, University of São Paulo. Accessed January 22, 2021. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-16042012-105910/ ;.

MLA Handbook (7^th Edition):

Aquino, Simone. “Efeitos da radiação gama no crescimento de aspergillus flavus produtor de aflatoxinas e no emprego da técnica da reação em cadeia da polimerase (PCR) em amostras de grãos de milho inoculadas artificialmente.” 2004. Web. 22 Jan 2021.

Vancouver:

Aquino S. Efeitos da radiação gama no crescimento de aspergillus flavus produtor de aflatoxinas e no emprego da técnica da reação em cadeia da polimerase (PCR) em amostras de grãos de milho inoculadas artificialmente. [Internet] [Masters thesis]. University of São Paulo; 2004. [cited 2021 Jan 22]. Available from: http://www.teses.usp.br/teses/disponiveis/85/85131/tde-16042012-105910/ ;.

Council of Science Editors:

Aquino S. Efeitos da radiação gama no crescimento de aspergillus flavus produtor de aflatoxinas e no emprego da técnica da reação em cadeia da polimerase (PCR) em amostras de grãos de milho inoculadas artificialmente. [Masters Thesis]. University of São Paulo; 2004. Available from: http://www.teses.usp.br/teses/disponiveis/85/85131/tde-16042012-105910/ ;

McMaster University

13. Safdar, Adeel. Endurance exercise-mediated therapeutic modulation of systemic mitochondrial biogenesis and genomic stability in aging.

Degree: PhD, 2011, McMaster University

URL: http://hdl.handle.net/11375/11291

►

Mitochondrial dysfunction and oxidative stress have been extensively characterized in aging. A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported… (more)

▼

Mitochondrial dysfunction and oxidative stress have been extensively characterized in aging. A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by studies demonstrating that the mtDNA mutator mouse, harbouring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits systemic mitochondrial dysfunction and phenocopies human aging. Epidemiological studies clearly demonstrate that endurance exercise reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline in aging remains elusive. This thesis examined the therapeutic effects of an active lifestyle in elderly individuals and forced endurance training in mtDNA mutator mouse model of aging. In older adults, a sedentary lifestyle was associated with reduced skeletal muscle mitochondrial function, dysregulated cellular redox status, and chronic systemic inflammation. Conversely, a physically active lifestyle compensated for aging-associated mitochondrial deterioration by preserving mitochondrial biogenesis, oxidative capacity, and redox status in skeletal muscle. To evaluate the systemic effects of endurance exercise, mutator mice were subjected to five months of treadmill training (15 m/min for 45 min, 3x/week). Endurance exercise conferred complete phenotypic protection and prevented premature mortality. The transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator (PGC)-1α is a critical regulator of mitochondrial biogenesis and is touted as a potential therapeutic target for aging-associated diseases. PGC-1α is dynamically regulated by post-transcriptional modification and sub-cellular compartmentalization. Endurance exercise activated PGC-1α regulated metabolic networks in the differentiated and proliferative compartments of the mutator mice, and thus promoted systemic mitochondrial biogenesis, prevented mtDNA mutations, reduced oxidative damage, attenuated telomere erosion and apoptosis markers. Mitochondrial-localized p53 facilitated mtDNA mutation repair despite the presence of defective polymerase gamma in these mice. These findings indicate that endurance exercise is an effective therapeutic approach to mitigate systemic mitochondrial dysfunction in aging, a feat that unmatched by an “exercise pill”.

Doctor of Science (PhD)

Advisors/Committee Members: Tarnopolsky, Mark A., Parise, Gianni, Raha, Sandeep, Kinesiology.

Subjects/Keywords: mitochondrial rejuvenation; aging; mtDNA; PGC-1a; telomere; mitochondrial polymerase gamma; Biochemical Phenomena, Metabolism, and Nutrition; Cellular and Molecular Physiology; Exercise Physiology; Geriatrics; Medical Molecular Biology; Medical Physiology; Sports Sciences; Systems and Integrative Physiology; Biochemical Phenomena, Metabolism, and Nutrition

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Safdar, A. (2011). Endurance exercise-mediated therapeutic modulation of systemic mitochondrial biogenesis and genomic stability in aging. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/11291

Chicago Manual of Style (16^th Edition):

Safdar, Adeel. “Endurance exercise-mediated therapeutic modulation of systemic mitochondrial biogenesis and genomic stability in aging.” 2011. Doctoral Dissertation, McMaster University. Accessed January 22, 2021. http://hdl.handle.net/11375/11291.

MLA Handbook (7^th Edition):

Safdar, Adeel. “Endurance exercise-mediated therapeutic modulation of systemic mitochondrial biogenesis and genomic stability in aging.” 2011. Web. 22 Jan 2021.

Vancouver:

Safdar A. Endurance exercise-mediated therapeutic modulation of systemic mitochondrial biogenesis and genomic stability in aging. [Internet] [Doctoral dissertation]. McMaster University; 2011. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/11375/11291.

Council of Science Editors:

Safdar A. Endurance exercise-mediated therapeutic modulation of systemic mitochondrial biogenesis and genomic stability in aging. [Doctoral Dissertation]. McMaster University; 2011. Available from: http://hdl.handle.net/11375/11291

University of Gothenburg / Göteborgs Universitet

14. Kollberg, Gittan. Crisis in Energy Metabolism - Mitochondrial Defects and a New Disease Entity.

Degree: 2006, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/779

► Impairment of energy metabolism may be associated with severe implications for affected individuals since all fundamental cell functions are energy-dependent. Disorders of energy metabolism are… (more)

▼ Impairment of energy metabolism may be associated with severe implications for affected individuals since all fundamental cell functions are energy-dependent. Disorders of energy metabolism are often genetic and associated with defects in the oxidative phosphorylation in mitochondria. This thesis addresses the pathogenesis in some mitochondrial disorders and a new disease entity associated with defects in the glycogen metabolism. In paper I we report on a primary mutation in mitochondrial DNA. We identified a T→C mutation at position 582 in the gene for tRNAPhe in a case of mitochondrial myopathy. The mutation alters a conserved base pairing in the aminoacyl stem of the tRNA. By analysis of single muscle fibers we showed that the level of heteroplasmy (proportion of mutant mtDNA) was higher in muscle fibers with defective cytochrome c oxidase (COX) activity compared to normal muscle fibers. Based on these findings we conclude that this mutation was responsible for the disease. In paper II we investigated a 30-year-old woman, who presented with an attack of acute rhabdomyolysis. We found an isolated deficiency of COX and a novel nonsense mutation in mtDNA in the gene encoding COX subunit I. In addition to its catalytic function, our data clearly indicates an important function of subunit I for the assembly of COX. The mutation was restricted to the patient’s muscle, but was not detectable in myoblasts, cultured from satellite cells isolated from affected muscle tissue. This result may have interesting implications for the natural evolution of the disease and perhaps therapy, since regenerating muscle occurs by proliferation of satellite cells. In paper III we investigated patients with mitochondrial diseases (progressive external ophthalmoplegia, PEO) due to primary mutations in POLG1 encoding mtDNA polymerase gamma (Polγ) and secondary multiple mtDNA deletions. The results show that it is very unlikely that mtDNA point mutations contribute to the pathogenesis in PEO patients with primary POLG1 mutations, and that the mechanism by which mutant Polγ cause mtDNA deletions does not involve mtDNA point mutations as an intermediate step, as has been previously proposed. In paper IV mtDNA alterations and pathology of muscle, brain and liver was investigated in children with Alpers-Huttenlocher syndrome (AHS), a fatal neurodegenerative disease associated with liver failure. All children had compound heterozygous missense mutations in POLG1. We provide evidence that AHS is a mitochondrial disease by demonstrating mtDNA alterations (reduced mtDNA copy number and multiple mtDNA deletions). Liver disease was triggered by valproate treatment in several cases possibly due to severe respiratory chain deficiency, which was demonstrated in liver tissue in one case. In paper V we report on a new disease entity “Muscle glycogen storage disease type zero” due to a homozygous stop mutation in the muscle glycogen synthase gene (GYS1). We performed investigations on a family where one child suffered sudden cardiac death at the age of…

Subjects/Keywords: Energy metabolism; Mitochondrial Disorders; mtDNA; multiple mtDNA deletions; Alpers-Huttenlocher syndrome; POLG1; GYS1; glycogen synthase; point mutation; Polymerase gamma

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APA (6^th Edition):

Kollberg, G. (2006). Crisis in Energy Metabolism - Mitochondrial Defects and a New Disease Entity. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/779

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kollberg, Gittan. “Crisis in Energy Metabolism - Mitochondrial Defects and a New Disease Entity.” 2006. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed January 22, 2021. http://hdl.handle.net/2077/779.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kollberg, Gittan. “Crisis in Energy Metabolism - Mitochondrial Defects and a New Disease Entity.” 2006. Web. 22 Jan 2021.

Vancouver:

Kollberg G. Crisis in Energy Metabolism - Mitochondrial Defects and a New Disease Entity. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2006. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/2077/779.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kollberg G. Crisis in Energy Metabolism - Mitochondrial Defects and a New Disease Entity. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2006. Available from: http://hdl.handle.net/2077/779

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Florida

15. Akhtar, Tariq. A Central Role for Gamma-Glutamyl Hydrolases in Plant Folate Metabolism.

Degree: PhD, Plant Molecular and Cellular Biology, 2010, University of Florida

URL: https://ufdc.ufl.edu/UFE0041594

► Animals cannot synthesize the B-vitamin folate and depend mainly on plants to supply them with this essential cofactor. The majority of plant folates, like those… (more)

Subjects/Keywords: Complementary DNA; Dimers; Enzymes; Metabolism; Monomers; Polymerase chain reaction; Protein isoforms; Signals; Tomatoes; Vacuoles; folate, gamma, heterodimer, polyglutamate, tomato, vacuole

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Akhtar, T. (2010). A Central Role for Gamma-Glutamyl Hydrolases in Plant Folate Metabolism. (Doctoral Dissertation). University of Florida. Retrieved from https://ufdc.ufl.edu/UFE0041594

Chicago Manual of Style (16^th Edition):

Akhtar, Tariq. “A Central Role for Gamma-Glutamyl Hydrolases in Plant Folate Metabolism.” 2010. Doctoral Dissertation, University of Florida. Accessed January 22, 2021. https://ufdc.ufl.edu/UFE0041594.

MLA Handbook (7^th Edition):

Akhtar, Tariq. “A Central Role for Gamma-Glutamyl Hydrolases in Plant Folate Metabolism.” 2010. Web. 22 Jan 2021.

Vancouver:

Akhtar T. A Central Role for Gamma-Glutamyl Hydrolases in Plant Folate Metabolism. [Internet] [Doctoral dissertation]. University of Florida; 2010. [cited 2021 Jan 22]. Available from: https://ufdc.ufl.edu/UFE0041594.

Council of Science Editors:

Akhtar T. A Central Role for Gamma-Glutamyl Hydrolases in Plant Folate Metabolism. [Doctoral Dissertation]. University of Florida; 2010. Available from: https://ufdc.ufl.edu/UFE0041594

16. Lee, Young-Sam. Structural and functional studies of the human mitochondrial DNA polymerase.

Degree: PhD, Cell and Molecular Biology, 2010, University of Texas – Austin

URL: http://hdl.handle.net/2152/ETD-UT-2010-08-1798

► The human mitochondrial DNA polymerase (Pol γ) catalyzes mitochondrial DNA synthesis, and thus is essential for the integrity of the organelle. Mutations of Pol γ… (more)

▼ The human mitochondrial DNA polymerase (Pol γ) catalyzes mitochondrial DNA synthesis, and thus is essential for the integrity of the organelle. Mutations of Pol γ have been implicated in more than 150 human diseases. Reduced Pol γ activity caused by inhibition of anti-HIV drugs targeted to HIV reverse transcriptase confers major drug toxicity. To illustrate the structural basis for mtDNA replication and facilitate rational design of antiviral drugs, I have determined the crystal structure of human Pol γ holoenzyme. The structure reveals heterotrimer architecture of Pol γ holoenzyme with a monomeric catalytic subunit Pol γA, and a dimeric processivity factor Pol γB. While the polymerase and exonuclease domains in Pol γA present high structural homology with the other members of the DNA Pol I family, the spacer between the two functional domains shows a unique fold, and constitutes the subunit interface. The structure suggests a novel mechanism for Pol γ’s high processivity of DNA replication. Furthermore, the structure reveals dissimilarity in the active sites between Pol γ and HIV RT, thereby indicating an exploitable space for design of less toxic anti-HIV drugs. Interestingly, the structure shows an asymmetric subunit interaction, that is, one monomer of dimeric Pol γB primarily participates in interactions with Pol γA. To understand the roles of each Pol γB monomer, I generated a monomeric human Pol γB variant by disrupting the dimeric interface of the subunit. Comparative studies of this variant and dimeric wild-type Pol γB reveal that each monomer in the dimeric Pol γB makes a distinct contribution to processivity: one monomer (proximal to Pol γA) increases DNA binding affinity whereas the other monomer (distal to Pol γA) enhances the rate of polymerization. The pol γ holoenzyme structure also gives a rationale to establish the genotypic-phenotypic relationship of many disease-implicated mutations, especially for those located outside of the conserved pol or exo domains. Using the structure as a guide, I characterized a substitution of Pol γA residue R232 that is located at the subunit interface but far from either active sites. Kinetic analyses reveal that the mutation has no effect on intrinsic Pol γA activity, but shows functional defects in the holoenzyme, including decreased polymerase activity and increased exonuclease activity, as well as reduced discrimination between mismatched and corrected base pair. Results provide a molecular rationale for the Pol γA-R232 substitution mediated mitochondrial diseases. Advisors/Committee Members: Yin, Yuhui Whitney (advisor), Molineux, Ian J. (committee member), Johnson, Kenneth A. (committee member), Paull, Tanya T. (committee member), Robertus, Jon D. (committee member).

Subjects/Keywords: Mitochondrial DNA polymerase; DNA replication; Mitochondrial disease; Drug toxicity; AIDS; mtDNA; Pol gamma holoenzyme

…polymerase (Pol γ) catalyzes mitochondrial DNA synthesis, and thus is essential for the… …1 Mitochondrial DNA polymerase (Pol γ)… …103 xiii Chapter 1: Introduction MITOCHONDRIAL DNA POLYMERASE (POL γ) DNA… …mitochondria. Because Pol γ is the sole DNA polymerase in mitochondria, mutations in Pol γ can cause… …Studies of the Human Mitochondrial DNA Polymerase Committee: Whitney Yin, Supervisor Ian…

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APA (6^th Edition):

Lee, Y. (2010). Structural and functional studies of the human mitochondrial DNA polymerase. (Doctoral Dissertation). University of Texas – Austin. Retrieved from http://hdl.handle.net/2152/ETD-UT-2010-08-1798

Chicago Manual of Style (16^th Edition):

Lee, Young-Sam. “Structural and functional studies of the human mitochondrial DNA polymerase.” 2010. Doctoral Dissertation, University of Texas – Austin. Accessed January 22, 2021. http://hdl.handle.net/2152/ETD-UT-2010-08-1798.

MLA Handbook (7^th Edition):

Lee, Young-Sam. “Structural and functional studies of the human mitochondrial DNA polymerase.” 2010. Web. 22 Jan 2021.

Vancouver:

Lee Y. Structural and functional studies of the human mitochondrial DNA polymerase. [Internet] [Doctoral dissertation]. University of Texas – Austin; 2010. [cited 2021 Jan 22]. Available from: http://hdl.handle.net/2152/ETD-UT-2010-08-1798.

Council of Science Editors:

Lee Y. Structural and functional studies of the human mitochondrial DNA polymerase. [Doctoral Dissertation]. University of Texas – Austin; 2010. Available from: http://hdl.handle.net/2152/ETD-UT-2010-08-1798

Queensland University of Technology

17. McDonald, Emily F. Expression of GABA receptors in human sclera.

Degree: 2014, Queensland University of Technology

URL: https://eprints.qut.edu.au/68604/

Subjects/Keywords: Gamma-Aminobutyric Acid (GABA); GABA Receptors; Sclera; Cultured Human Scleral Cells; Reverse-Transcriptase Polymerase Chain Reaction; Choroid; Retinal Pigment Epithelium; Retina; Eye

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

McDonald, E. F. (2014). Expression of GABA receptors in human sclera. (Thesis). Queensland University of Technology. Retrieved from https://eprints.qut.edu.au/68604/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

McDonald, Emily F. “Expression of GABA receptors in human sclera.” 2014. Thesis, Queensland University of Technology. Accessed January 22, 2021. https://eprints.qut.edu.au/68604/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

McDonald, Emily F. “Expression of GABA receptors in human sclera.” 2014. Web. 22 Jan 2021.

Vancouver:

McDonald EF. Expression of GABA receptors in human sclera. [Internet] [Thesis]. Queensland University of Technology; 2014. [cited 2021 Jan 22]. Available from: https://eprints.qut.edu.au/68604/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

McDonald EF. Expression of GABA receptors in human sclera. [Thesis]. Queensland University of Technology; 2014. Available from: https://eprints.qut.edu.au/68604/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

18. Seno, Kei; Ohno, Jun; Ota, Nobutaka; Hirofuji, Takao. Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. : Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats.

Degree: 博士（歯学）, 2016, Fukuoka Dental College / 福岡歯科大学

URL: http://id.nii.ac.jp/1167/00000040/

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BACKGROUND:Administration of mercury at nontoxic doses induces systemic autoimmune disease in Brown Norway (BN) rats. The pathogenesis of lupus-like oral mucosal lesion by mercury-induced autoimmunity… (more)

Subjects/Keywords: 水銀誘導型自己免疫応答; 口腔粘膜; ループス様病変; Brown Norwayラット; マクロファージ; Animals; Antigens, CD5; Autoimmune Diseases; Autoimmunity; Basement Membrane; Dendritic Cells; Epithelium; Gene Expression; Histocompatibility Antigens Class II; Immunohistochemistry; Injections, Subcutaneous; Interferon-gamma; Interleukin-4; Kidney; Macrophages; Male; Mercury; Mouth Mucosa; Rats; Rats, Inbred BN; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Time Factors; Tongue; Mercury-induced autoimmunity; Oral mucosa; Lupus-like lesions; Brown Norway rats

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Seno, Kei; Ohno, Jun; Ota, Nobutaka; Hirofuji, T. (2016). Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. : Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. (Thesis). Fukuoka Dental College / 福岡歯科大学. Retrieved from http://id.nii.ac.jp/1167/00000040/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Seno, Kei; Ohno, Jun; Ota, Nobutaka; Hirofuji, Takao. “Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. : Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats.” 2016. Thesis, Fukuoka Dental College / 福岡歯科大学. Accessed January 22, 2021. http://id.nii.ac.jp/1167/00000040/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Seno, Kei; Ohno, Jun; Ota, Nobutaka; Hirofuji, Takao. “Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. : Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats.” 2016. Web. 22 Jan 2021.

Vancouver:

Seno, Kei; Ohno, Jun; Ota, Nobutaka; Hirofuji T. Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. : Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. [Internet] [Thesis]. Fukuoka Dental College / 福岡歯科大学; 2016. [cited 2021 Jan 22]. Available from: http://id.nii.ac.jp/1167/00000040/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Seno, Kei; Ohno, Jun; Ota, Nobutaka; Hirofuji T. Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. : Lupus-like oral mucosal lesions in mercury-induced autoimmune response in Brown Norway rats. [Thesis]. Fukuoka Dental College / 福岡歯科大学; 2016. Available from: http://id.nii.ac.jp/1167/00000040/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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Open Access Theses and Dissertations