Dissertations / Theses on the topic 'DNA repair'
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1
Moorwood, Kim. "DNA mismatch repair." Thesis, University of Sussex, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580146.
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White, C. I. "DNA repair in yeast." Thesis, Open University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333151.
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Boal, Amie Kathleen Parker Carl Stevens Barton Jacqueline K. "DNA-mediated charge transport in DNA repair /." Diss., Pasadena, Calif. : California Institute of Technology, 2008. http://resolver.caltech.edu/CaltechETD:etd-06022008-092549.
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Carson, Christian Tyler. "DNA viruses and the cellular DNA repair machinery /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3175282.
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Clever, Beate. "DNA repair in eukaryotes: the Rad54 recombinational repair protein /." [S.l : s.n.], 1996. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Hoffbeck, Anne-Sophie. "Chromatin structure and DNA repair." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ104/document.
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Notre génome est continuellement endommagé par des agents provoquant des lésions de l’ADN. Les cassures doubles brins de l’ADN (CDBs) sont les lésions les plus dangereuses. En effet, une CDB mal réparée peut mener à des aberrations de l’ADN pouvant conduire à l’apparition d’un cancer. Dans le but d’éviter les effets délétères des CDBs, nos cellules ont développé une voie de signalisation, nommée réponse aux dommages de l’ADN (RDA), permettant la détection des cassures et l’activation des points de contrôle du cycle cellulaire afin d’arrêter le cycle pendant la réparation des CDBs. Une des caractéristiques principales de la RDA est l’accumulation d’un grand nombre de facteurs sur l’ADN autour de la cassure, formant un foyer visible en microscopie. Cependant, l’efficacité de réparation de l’ADN est entravée par la structure condensée de la chromatine environnante. Les mécanismes de réparation de l’ADN surmontent ce problème en recrutant de nombreuses protéines permettant le réarrangement de la chromatine afin de faciliter la réparation. Le but de mon travail de thèse est d’identifier de nouvelles protéines impliquées dans le remodelage de la chromatine autour des CDBs. D’une part nous avons pour but d’identifier le protéome complet d’un foyer de réparation de l’ADN grâce à la technique PICh (Proteomics of Isolated Chromatin loci). D’autre part, nous étudions le rôle de l’oncoprotéine SET/TAF-1β, que nous avons identifié lors d’un criblage siRNA réalisé dans le but de découvrir de nouveaux facteurs chromatiniens impliqués dans la réparation des CDBsVarious DNA damaging agents, that can cause DNA lesions, assault constantly our genome. The most deleterious DNA lesions are the breaks occurring in both strands of DNA (Double stand breaks: DSBs). Inefficient repair of DSBs can lead to aberrations that may induce cancer. To avoid these deleterious effects of DSBs, cells have developed signalling cascades which entail detection of the lesions and spreading of the signal that leads to arrest in cell cycle progression and efficient repair. A major characteristic of DNA damage response (DDR) is the accumulation of a vast amount of proteins around the DSBs that are visible in the cell as DNA damage foci. However, efficient DNA repair is hampered by the fact that genomic DNA is packaged into chromatin. The DNA repair machinery overcomes this condensed structure to access damaged DNA by recruiting many proteins that remodel chromatin to facilitate efficient repair. The aim of my PhD work is to identify novel proteinsinvolved in the DDR and/or the remodelling of chromatin surrounding DSBs. On one hand, we take advantage of the PICh (Proteomics of Isolated Chromatin loci) technique and we aim to identify the entire proteome of DNA repair foci. On the other hand, we study the role of the oncogene SET/TAFIβ, a major hit of a siRNA screen performed to identify novel chromatin related proteins that play role in repair of DSBs
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Clark, Graeme T. "A study of DNA repair." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302000.
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Steffens, Laura Sione. "DNA repair in bacteroides fragilis." Master's thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/4337.
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Includes abstract.Includes bibliographical leaves (leaves 89-101).
Bacteroides fragilis is a gut commensal in both humans and animals where it benefits the host through metabolizing indigestible compounds, stimulating the immune system and protecting against pathogen colonization. However, it is also an opportunistic pathogen, responsible for approximately half of anaerobic bacteraemias. Metronidazole is used to treat anaerobic infections. It diffuses into the celI as an inactive prodrug where it is reduced to form nitro anion and nitroso and hydroxylamine radicals. These chemically reactive compounds interact with DNA causing strand breaks and base mutations; the damage accumulates and leads to cell death. Mechanisms of metronidazole resistance in B. fragilis include decreased activity of oxidation/reduction enzymes, over-expression of multidrug efflux pumps and the conversion of metronidazole to non-toxic derivatives by nitroimidazole nitroreductases (encoded by nim genes). However, metronidazole resistance could also potentialIy be mediated by the over-expression or enhanced activity of DNA repair proteins. Thus, DNA repair in B. fragilis should be thoroughly investigated.
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Mackenney, Victoria Jane. "Human DNA ligase I in DNA replication and repair." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267515.
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Gould, Poppy Aeron. "The role of DNA repair in DNA methylation dynamics." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/274360.
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The mammalian epigenome is globally reprogrammed at two stages of development; this involves the erasure and re-establishment of DNA methylation by both passive and active mechanisms, including DNA repair pathways, and occurs concurrently with an increase in developmental potency. In addition to Uhrf1 and the Tet enzymes, the interplay between activation induced cytidine deaminase (AID) and the DNA repair machinery has been implicated in epigenetic reprogramming of various in vivo and in vitro systems including mouse primordial germ cells, zygotes and induced pluripotent stem cells. AID deaminates cytosine to uracil and can also deaminate methylcytosine, whereas the primary role of UNG is to maintain the integrity of the genome through erasure of uracil. In this thesis, I have aimed to investigate the role of DNA repair in demethylation. To do this I have focused on the specific role of AID and UNG in the demethylation of a static system – primed serum ESCs and a dynamic system – serum to 2i (naïve) to epiblast-like ES cells. As the role of both AID and UNG involves genomic uracil, the central theme of my thesis is the impact of accumulation of uracil on DNA methylation levels in the genome. Therefore, my first aim was to develop a quantitative method to detect low levels of genomic uracil in DNA firstly, by mass spectrometry and secondly, by whole genome sequencing. In Chapter Three, I show that the impact of deamination during DNA preparation can be minimised, such that the level of genomic ESC uracil can be accurately determined as around 12,000 uracil per genome and that, as anticipated, Ung null ESCs have almost twice the genomic uracil content of wildtype ESCs. Secondly, I address the main question which is the impact of uracil accumulation on methylation levels. In order to do this, I generate two cell lines: Ung knockout and Aid over expressing, both of which should result in an increase in genomic uracil. I demonstrate that while over expression of Aid stimulates demethylation in static system and in a dynamic demethylating system, the impact of Ung knockout is less clear. In (static) serum ESCs, loss of Ung results in hypomethylation however, in order to transition to 2i (naïve) ESCs, a process which involves demethylation of the genome, it appears the Ung is required as loss of this gene inhibits proper demethylation. As such, I conclude that UNG-mediated DNA repair functions alongside passive demethylation, by reduction of UHRF1 levels, to demethylate 2i ESCs. To probe the mechanism by which accumulation of uracil in the genome alters methylation levels, I investigate the impact of Ung KO and Aid OE on global levels of DNA damage. I show that both cell lines have a greater incidence of double strand breaks compared to a wild type cell line, and accordingly, upregulate their DNA damage response pathway and the expression of certain repair genes. I suggest that increasing genomic levels of uracil causes genomic instability and that DNA demethylation occurs as a consequence of the repair of extensive DNA damage. More broadly, I suggest that ESCs are uniquely poised, due to their heightened DNA damage response, to use uracil as an intermediate of DNA demethylation. Interestingly, I also note that the biological impact on serum ESCs of loss of Ung appears to be an increase in pluripotency.
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Zheng, Yi. "Nucleotide excision repair in mammalian cells /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Prendergast, James G. D. "Cancer, DNA repair and chromatin structure." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/29328.
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In this project we have adopted a number of approaches to try and further characterise the genetic contribution of colorectal cancer. To begin to understand tumour progression we first characterised the gene expression changes observed in various tumours using SAGE, EST and microarray data. Although many genes were identified as differentially expressed in cancers, little congruence was observed between tumour types and even expression platforms. We next compared gene expression changes observed along chromosomes to local chromatin structure, and showed that regions of constitutively open structure generally shown an increase in gene expression in cancer. Despite the lack of congruence between expression data shown previously, we illustrated that such a correlation between gene expression change in tumours and chromatin structure can be observed using various expression platforms and across a variety of tumours. To further characterise the role of chromatin structure in tumours we also investigated the rates of mutation and selection across chromatin categories. DNA damage and repair is a key process in cancer progression and we have shown, through inter species alignments, that although chromosomal regions of a relatively more open chromatin structure undergo lower rates of mutation, levels of purifying selection on synonymous sites are highest in regions of closed chromatin. As part of the COGS/SOCCS group the role of DNA repair in colorectal cancer was finally further investigated through a case-control association study. Tagging SNPs in genes predicted to be associated with DNA repair were selected and subsequently typed by the group in approximately 1000 cases and 1000 controls. The nature of SNPs with evidence of an association with colorectal cancer was finally characterised.
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Dunn, Alison M. "Cloning of human DNA repair genes." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301385.
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Rothwell, Dominic G. "Characterisation of human DNA repair proteins." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364145.
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Walker, Lisa J. "HAP1 : a human DNA repair enzyme." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386682.
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Sleeth, Kate Michelle. "DNA ligases in base excision repair." Thesis, University of Reading, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428317.
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Ahnesorg, Peter. "Molecular genetic analysis of DNA repair." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614127.
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Liccardi, G. "Nuclear EGFR modulation of DNA repair." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1335897/.
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Overexpression of the epidermal growth factor receptor (EGFR) is associated with resistance to chemotherapy and radiotherapy. EGFR involvement, in repair of radiation-induced DNA damage, is mediated by association with the catalytic subunit of DNA protein kinase (DNAPKcs). This study investigated the role of EGFR nuclear import, and its association with DNAPKcs, on DNA repair following treatment either with cisplatin or ionizing radiation (IR). EGFR- null murine NIH3T3 cells were transfected with wild type or with mutated EGFR (mutations found in human cancers L858R, EGFRvIII and mutations in the EGFR nuclear localization signal (NLS) sequence NLS123, LNLS123). Comet assay analysis, which measures unhooking of cisplatin crosslinks and repair of IR induced strand breaks, demonstrated that wtEGFR and EGFRvIII completely repair cisplatin and IR induced DNA damage. Immunoprecipitation studies show that repair is associated with the binding of both wtEGFR and EGFRvIII to DNAPKcs, which increases by 2- fold 18 hours following cisplatin treatment. Confocal analysis and proximity ligation assay indicated that this association takes place both in the cytoplasm and in the nucleus resulting in a significant increase of DNA-PK kinase activity. Intermediate levels of repair as shown by the L858R construct with impaired nuclear localization demonstrated that EGFR kinase activity is partially involved in repair but is not sufficient to determine EGFR nuclear expression. EGFR-NLS mutants showed impaired nuclear localization and impaired DNAPKcs association resulting in significant inhibition of DNA repair and downregulation of DNA-PK kinase activity. Our data suggest that EGFR nuclear localization is required for the modulation of cisplatin and IR induced DNA damage repair. The EGFR-DNAPKcs binding is triggered by cisplatin or IR and not by EGFR nuclear translocation per se. Understanding mechanisms regulating EGFR subcellular distribution in relation to DNA repair kinetics will be a critical determinant of improved molecular targeting and response to therapy.
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Hengel, Sarah Ruth. "Dissecting RAD52 function in DNA repair." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5773.
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Defects in BRCA1 and BRCA2 tumor suppressors predispose one to breast and ovarian cancer. The current treatment for BRCA-deficient cancers is mastectomy. Because both copies of the tumor suppressor need to be defective for cancer to occur, identifying cellular mechanisms that specifically target BRCA-deficient cells is of paramount importance. Luckily, recent experiments have shown that depletion of a protein named RAD52 in BRCA1 or BRCA2 cancer cells causes them to die. Therefore, we can use small molecules to stop the RAD52 protein from functioning. We need, however, to know which of the RAD52 activities to inhibit and how. One function of RAD52 that likely underlies all cellular activities is its ability to bind single-stranded DNA (ssDNA). To identify if small molecules could inhibit the RAD52-ssDNA complex, I screened a small library of compounds and found 13 potential inhibitors. We validated that these small molecules bind to RAD52 and inhibit RAD52 DNA binding and annealing activities. The identification of these small molecules is important because we can use them to dissect the function of RAD52 in normal and malignant cells, which to date remains elusive.
In an attempt to further advance our understanding of RAD52 function and regulation we are also investigating how a novel binding partner, DSS1, interacts with RAD52 and modulates its activities. My data show that this protein enhances the way RAD52 finds separate complementary DNA templates and anneals them to make a double-stranded product. At least in part, these studies have identified some residues likely involved in the binding site of DSS1 on RAD52. In aggregate, the outcome of the two projects deepens our understanding of the complex and interconnected cellular pathways that support the integrity of genomes.
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Chaim, Isaac Alexander. "Functional DNA repair capacity assays : a focus on base excision repair." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104221.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2016.Cataloged from PDF version of thesis.
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The integrity of our DNA is challenged by roughly 100,000 lesions per cell on a daily basis. Failure to cope with DNA damage can lead to cancer, immunodeficiency and degenerative disease. Quantitating and understanding an individual's DNA repair capacity may enable us to predict and prevent disease in a personalized manner. Base Excision Repair (BER) is known for the recognition and repair of endogenous and exogenous mutagenic non-helix-distorting lesions produced by DNA base alkylation, deamination and oxidation. BER is initiated by the action of one of eleven DNA glycosylases known-to-date. Many studies have shown that levels of these glycosylases can vary between individuals, suggesting a basis for inter-individual differences in DNA repair capacity. Moreover, the methods for measuring DNA repair capacity used so far are cumbersome, time consuming, low throughput and only allow for the analysis of one glycosylase at a time. We have taken a fluorescence-based multiplex flow-cytometric host cell reactivation assay wherein the activity of several DNA glycosylases and their immediate downstream endonuclease (APE1) can be tested simultaneously, at single-cell resolution, under physiological conditions. Taking advantage of the transcriptional properties of several DNA lesions we have designed and engineered specific fluorescent reporter plasmids for OGG1, AAG, MUTYH, UNG and APE1. Inter-individual differences in DNA repair capacity of a panel of cell lines derived from healthy individuals have been measured. Regression models that incorporate these measurements have been developed in order to predict cellular sensitivity to the chemotherapeutic and DNA damaging agents 5-FU, H₂O₂ and MMS, with the interest of understanding the contributions that these differences can have on personalized disease prevention and treatment. Finally, we have conducted a pilot population study with 56 healthy subjects where we implemented all the methods developed in order to determine the feasibility of measuring DNA repair capacity variations in a healthy human population. Additionally, we report the discovery of a novel in vivo role of the TC-NER pathway in the repair of the lipid-peroxidation product, 3,N⁴-etheno-cytosine.
by Isaac Alexander Chaim.
Ph. D.
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Krusong, Kuakarun. "Recognition and repair of DNA damage by uracil DNA glycosylase." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417133.
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Cooley, Nicola. "Quantitative associations betweenn DNA damage, DNA repair and celluar outcomes." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.499845.
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Meagher, Martin. "Role of tyrosyl-DNA-phosphodiesterase I in mitochondrial DNA repair." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/1940.
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The mechanisms for DNA repair in mitochondria is an area in which there is limited knowledge in comparison to the DNA repair mechanisms that have been defined in the nucleus. Although it is understood that mitochondria have less DNA repair mechanisms than in the nucleus there is still a lot more scope for identifying new proteins involved in the repair of mitochondrial DNA (mtDNA). The main focus of this thesis was to attempt to determine whether there was presence and activity of a DNA repair enzyme in mitochondria, namely tyrosyl-DNA-phosphodiesterase 1 (TDP1), and if so what is the exact role of this enzyme in mtDNA repair. This enzyme has already been characterised as an single strand break repair (SSBR) enzyme in the nucleus, and a mutation in this gene can cause the autosomal recessive disorder spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). The data in this thesis provides evidence for the presence and activity of TDP1 in mitochondria and that the function of this enzyme on mtDNA is most likely limited to the removal of mitochondrial topoisomerase 1 (TOP1mt). It has also been shown that phosphorylation of amino acid 81 of TDP1 does not facilitate its interaction with DNA ligase 3α in mitochondria and that there most probably no direct link between these enzymes in this organelle, unlike that found in the nucleus. This data indicates that there is still potential for identification of more enzymes that are involved in mtDNA repair.
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Valsecchi, Isabel. "AtZDP, a Plant 3' DNA Phosphatase, Involved in DNA Repair." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8907.
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Kaliyaperumal, Saravanan. "hMSH6 Protein Phosphorylation: DNA Mismatch Repair or DNA Damage Signaling?" Connect to full text in OhioLINK ETD Center, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1242933021.
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Dissertation (Ph.D.)--University of Toledo, 2009."In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Bibliography: p. 174-180, p. 201-238.
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Robertson, Adam Brian Matson Steve. "MutL involvement in two DNA repair pathways methyl-directed mismatch repair and very short patch repair /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1427.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Apr. 25, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biology." Discipline: Biology; Department/School: Biology.
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Vonarx, Edward J., and mikewood@deakin edu au. "The repair and tolerance of DNA damage in higher plants." Deakin University. School of Biological and Chemical Sciences, 2000. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20051110.135641.
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DNA repair mechanisms constitute an essential cellular response to DNA damage arising either from metabolic processes or from environmental sources such as ultraviolet radiation. Repair of these lesions may be via direct reversal, or by processes such as nucleotide excision repair (NER), a coordinated pathway in which lesions and the surrounding nucleotides are excised and replaced via DNA resynthesis. The importance of repair is illustrated by human disease states such as xeroderma pigmentosum and Cockayne's syndrome which result from defects in the NER system arising from mutations in XP- genes or XP- and CS- genes respectively
Little detail is known of DNA damage repair processes in plants, despite the economic and ecological importance of these organisms. This study aimed to expand our knowledge of the process of NER in plants, largely via a polymerase chain reaction (PCR)-based approach involving amplification, cloning and characterisation of plant genomic DNA and cDNA. Homologues of the NER components XPF/RAD1 and XPD/RAD3 were isolated as both genomic and complete cDNA sequences from the model dicotyledonous plant Arabidopsis thaliana. The sequence of the 3'-untranslated region of atXPD was also determined. Comparison of genomic and cDNA sequences allowed a detailed analysis of gene structures, including details of intron/exon processing. Variable transcript processing to produce three distinct transcripts was found in the case of atXPF. In an attempt to validate the proposed homologous function of these cDNAs, assays to test complementation of resistance to ultraviolet radiation in the relevant yeast mutants were performed. Despite extensive amino acid sequence conservation, neither plant cDNA was able to restore UV-resistance. As the yeast RAD3 gene product is also involved in vivo in transcription, and so is required for viability, the atXPD cDNA was tested in a complementation assay for this function in an appropriate yeast mutant. The plant cDNA was found to substantially increase the viability of the yeast mutant.
The structural and functional significance of these results is discussed comparatively with reference to yeast, human and other known homologues. Other putative NER homologues were identified in A. thaliana database sequences, including those of ERCC1/RAD10 and XPG/ERCC5/RAD2, and are now the subjects of ongoing investigations. This study also describes preliminary investigations of putative REVS and RAD30 translesion synthesis genes from A. thaliana.
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Pospiech, H. (Helmut). "The role of DNA polymerases, in particular DNA polymerase ε in DNA repair and replication." Doctoral thesis, University of Oulu, 2002. http://urn.fi/urn:isbn:9514266692.
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Abstract
Analysis of the primary structure of DNA polymerase ε B subunit
defined similarities to B subunits of eukaryotic DNA polymerases α,
δ and ε as well as the small subunits of DNA polymerase DI of
Euryarchaeota. Multiple sequence alignment of these proteins revealed the
presence of 12 conserved motifs and defined a novel protein superfamily.
The members of the B subunit family share a common domain architecture,
suggesting a similar fold, and arguing for a conserved function among
these proteins.
The contribution of human DNA polymerase ε to nuclear DNA
replication was studied using the antibody K18 that specifically inhibits
the activity of this enzyme in vitro. This antibody
significantly inhibited DNA synthesis both when microinjected into nuclei
of exponentially growing human fibroblasts and in isolated HeLa cell
nuclei, but did not inhibit SV40 DNA replication in
vitro. These results suggest that the human DNA polymerase
ε contributes substantially to the replicative synthesis of DNA and
emphasises the differences between cellular replication and viral model
systems.
The human DNA polymerases ε and δ were found capable of
gap-filling DNA synthesis during nucleotide excision repair in
vitro. Both enzymes required PCNA and the clamp loader RFC, and
in addition, polymerase δ required Fen-1 to prevent excessive
displacement synthesis. Nucleotide excision repair of a defined DNA lesion
was completely reconstituted utilising largely recombinant proteins, only
ligase I and DNA polymerases δ and ε provided as highly purified
human enzymes. This system was also utilised to study the role of the
transcription factor II H during repair.
Human non-homologous end joining of model substrates with different
DNA end configurations was studied in HeLa cell extracts. This process
depended partially on DNA synthesis as an aphidicolin-dependent DNA
polymerase was required for the formation of a subset of end joining
products. Experiments with neutralising antibodies reveal that DNA
polymerase α but not DNA polymerases β or ε, may represent
this DNA polymerase activity. Our results indicate that DNA synthesis
contributes to the stability of DNA ends, and influences both the
efficiency and outcome of the end joining event. Furthermore, our results
suggest a minor role of PCNA in non-homologous end joining.
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Bajinskis, Ainars. "Studies of DNA repair strategies in response to complex DNA damages." Doctoral thesis, Stockholms universitet, Institutionen för genetik, mikrobiologi och toxikologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-72472.
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The main aim of this thesis was to study the role of the indirect actions of γ-rays and α-particles on the complexity of primary DNA damages and the repair fidelity of major DNA repair pathways: non-homologous end joining (NHEJ), homologous recombination repair (HRR) and base excision repair (BER). The complexity of radiation-induced damages increases and the proximity between damages decreases with increasing LET due to formation of ionization clusters along the particle track. The complexity of damages formed can be modified by the free radical scavenger dimethyl sulfoxide (DMSO). In addition, the effects of low doses of low dose rate γ-radiation on cellular response in terms of differentiation were investigated. Paper I investigates the role of the indirect effect of radiation on repair fidelity of HRR, NHEJ and BER when damages of different complexity were induced by radiation or by potassium bromate. We found that potassium bromate induces complex DNA damages through processing of base modifications and that the indirect effect of radiation has a high impact on the NHEJ pathway. Results in paper II confirmed our conclusions in paper I that the indirect effect from both γ-rays and α-particles has an impact on all three repair pathways studied and NHEJ benefits the most when the indirect effect of radiation is removed. In paper III we investigated the effects of low dose/dose rate γ-radiation on the developmental process of neural cells by using cell models for neurons and astrocytes. Our results suggest that low dose/dose rate γ-radiation attenuates differentiation and down-regulates proteins involved in the differentiation process of neural cells by an epigenetic rather than cytotoxic mechanism.At the time of doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.
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Massey, Andrew James. "DNA repair and the cytotoxic effects of cisplatin and DNA thiobases." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395114.
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Cobb, Andrew Martin. "Resolving the flexibility and intricacy of DNA repair protein-DNA interactions." Thesis, University of East Anglia, 2010. https://ueaeprints.uea.ac.uk/10586/.
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Within all cells, complex molecular systems exist that are responsible for maintaining genome stability by detecting and repairing dangerous alterations in DNA. Ensuring the accurate and efficient functioning of such systems is necessary for the preservation of DNA integrity and avoidance of disease. The flexible and diverse modes of DNA-binding exhibited by human p53 permits this ‘guardian of the genome’ to elicit versatile cellular activities that are crucial in monitoring threats to genome dynamics and conducting appropriate responses. In conjunction with its sequence-specific DNA-binding activity that is essential to target gene transactivation, p53 can bind to unusual DNA structures independent of DNA sequence and it has been proposed this activity may allow p53 to interact with detrimental secondary structures that arise in unstable genomic regions. To provide further insight into p53-DNA interactions, an in vitro DNA binding assay was developed that was used to characterise binding properties towards several DNA molecules to allow comparison of non-specific, sequence-specific and structurespecific binding. It was determined that unusual structures in DNA significantly enhanced p53 binding in non-sequence specific DNA and that the presence of internal hairpin regions induced binding comparable to sequence-specific binding. In vivo p53-DNA interactions were also quantified using chromatin immunoprecipitation and variations in preference to different response element sequences was ascertained. DNA binding is also central to the ability of Ku proteins to function as essential components of non-homologous end joining and telomere maintenance in eukaryotes. Prokaryotic homologues of Ku proteins that function as homodimers in two-component repair systems have also been identified. Recently, 3 Ku homologues in Streptomyces coelicolor were reported, but very little is currently known regarding their biological activity. It was discovered that all 3 Ku proteins exhibited varied independent DNA-binding properties that were influenced by DNA topology, size and end-structure. Unusually for Ku, it was found 1 of these proteins exhibited strong binding to single-stranded DNA. Precipitation assays determined that these proteins may act as DNA end synapsis mediators during the DNA endjoining process and ligation experiments revealed Ku was responsible for rigidifying DNAs or completely inhibiting ligation activity, probably via DNA end-protection activity. Experimental evidence indicated that specific interactions could occur between S. coelicolor Ku suggesting these proteins form both homodimers and heterodimers.
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Karakoula, Aikaterini. "Studies on UV-induced DNA damage and repair to human DNA." Thesis, University of Leicester, 2004. http://hdl.handle.net/2381/29692.
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The induction and repair of DNA damage has been shown to occur heterogeneously throughout the mammalian genome. As a consequence, analysis of these parameters at a global genome level may not reflect important gene-level events. Few techniques have been established to explore quantitatively gene-specific DNA damage and repair. Most of these are PCR-based assays and are relatively insensitive, relying on decreased PCR amplification arising from damage in template DNA. In this study, a quantitative assay that combines specific immunocapture of damaged DNA by an antiserum specific for thymine dimers (IgG479), with PCR amplification of a 149bp fragment of the human H-ras proto-oncogene was established. Quantification of DNA damage was based upon proportionality between the amount of the PCR product and the initial amount of damage. Detection of thymine dimers was possible with nanogram amounts of genomic DNA and increased in a linear, dose-responsive manner. Using this assay, gene-level induction of thymine dimers was shown to be directly proportional to levels induced in the global genome of UVC-and-UVB-irradiated genomic DNA, as measured by gas chromatography-mass spectrometry and enzyme-linked immunosorbent assay, respectively. This result suggests that global damage assessments do indeed reflect gene-level events. However, preferential repair of UVB-induced T < > T from the human H-ras proto-oncogene than the overall genome of human keratinocyte cells was detected. These findings demonstrate the suitability of this approach to the detection of UVR-induced DNA damage and repair at the level of individual genes.
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Camacho, Inês Sofia Cortes Eusébio. "Effects of UV radiation exposure on DNA and DNA repair enzymes." Master's thesis, Faculdade de Ciências e Tecnologia, 2012. http://hdl.handle.net/10362/8263.
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Dissertação para obtenção do Grau de Mestre em
BiotecnologiaDNA integrity in the cell is under constant threat from damaging agents of endogenous or exogenous origin, such as UV light, ionizing radiation and oxidative stress. Although the effects of these carcinogens on DNA have been extensively studied, very little is known about their effect on DNA repair enzymes. The aim of the present work was the study of the effect of UV radiation on E. coli Endonuclease III, a DNA glycosylase belonging to base excision repair system. This enzyme was homologously overexpressed and then purified with a Fe/protein ratio of 3.88 ± 0.63 (fully‐loaded form). Endonuclease III exposure to UV radiation for 45 min (19.77 kJ dose) may lead to the destruction of the Fe‐S bonds of the [4Fe‐4S] cluster or to the conversion of this center into a different redox state. Electrophoretic mobility shift assays with protein‐DNA complex showed that Endonuclease III binding to plasmid DNA promotes a retardation of the free supercoiled DNA band, indicative of Endonuclease III‐DNA complex(es) formation. These assays also showed that Endonuclease III is able to bind both linear and supercoiled plasmid DNA, although with higher affinity for the linear form. Electrophoretic mobility shift assays performed after 45 min of UV irradiation (19.77 kJ) revealed that although shift occurred, the complexes formed were unstable and dissociated during electrophoresis. Moreover, the presence of aggregates suggests the unfolding of some Endonuclease III molecules. After 6 h of UV irradiation (158.18 kJ) no complexes are formed, leading to the conclusion that Endonuclease III molecules were irreversibly damaged. The electrochemical studies were performed by cyclic and differential pulse voltammetry techniques, at room temperature and anaerobic conditions; Endonuclease III and Endonuclease IIIDNA complex were adsorbed on a bare pyrolytic graphite electrode. For the first time, the direct electrochemical response of Endonuclease III unbound to DNA was observed, with a quasi‐reversible redox couple displaying a midpoint potential of 178 ± 9 mV vs. NHE. Endonuclease III binding to plasmid DNA promotes a positive shift (19 mV vs. NHE) in the characteristic redox couple of Endo III. Protein‐DNA complex UV irradiation promotes a negative shift in its redox potential of 25 mV vs. NHE.
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Stracker, Travis Hileman. "DNA virus interactions with host cell DNA replication and repair pathways /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2002. http://wwwlib.umi.com/cr/ucsd/fullcit?p3070999.
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Karthikraj, Karthikraj. "Crosstalk between DNA repair and chromatin modifications." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-194964.
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Chambers, Scott R. "DNA mismatch repair and meiotic homeologous recombination." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302524.
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Loughery, Jayne Eleanor Patricia. "Mismatch repair, DNA methylation and cell death." Thesis, University of Ulster, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.551565.
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Mismatch repair is a vital DNA repair mechanism whose absence leads to a tolerance towards mutations and a predisposition to colon cancer. MLHl is one of the main proteins involved and is highly conserved from E. coli to human. It not only plays a role in repair, but can signal the cell to die if damage levels become too high. The mechanism by which MLHl triggers cell death in response to damage is not entirely clear, and is likely to differ between normal and cancerous cells. Previous work in the Walsh lab had generated MLH1-depleted subclones of a telomerase- immortalised normal human fibroblast cell line. These had been generated by transfecting the parental line hTERT-1604 with an shRNA vector against MLHl and selecting subclones which had reduction in MLHl to various degrees. I further characterised these MLHl knockdown cell lines and revealed that they also exhibit resistance to the methylating agent N-Methyl-N-Nitrosourea. Through the use of various assays we were able to determine that the hTERT immortalised cells did not undergo cell cycle arrest, apoptosis or senescence in response to MNU as colon cancer cell do. Instead, they undergo an MLH1-dependant form of programmed cell death mediated by PARP, but independent of caspase, P53 and ATM/ATR. In 2004, DNMTl deficiency was also implicated in causing MMR defects in mouse embryonic stem cells without a causal mechanism being identified. The effects of DNMTl deficiency are not the same in stem cells and differentiated cells. To determine if depletion of DNMTl can also cause MMR defects in normal human cells, I created DNMT1-depleted hTERT-1604 cells using the same shRNA-mediated strategy as above. Subsequent characterisation of the DNMT1-depleted subclones established that they have a reduction in DNA methylation and the most severely reduced cells are arrested at the G2/M checkpoint. Subclones with significant reductions in DNMT1 also exhibited a decrease in MLH1 expression at the protein, but not the mRNA level. This reduction in MLH1 expression was reversed when a protease inhibitor was employed. The subclone with 31% DNMT1 expression exhibited microsatellite instability, providing further evidence for an interaction between mismatch repair and DNMT1 in human cells and suggesting a mechanism by which this may occur. In conclusion, the work presented here demonstrates a novel role for the mismatch repair protein MLH1 in triggering PARP-dependent cell death in response to damage by MNU. It also shows a link between DNMT1 depletion and MMR deficiency through destabilisation of MLH1.
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Trautinger, Brigitte W. "Interplay between DNA replication, transcription and repair." Thesis, University of Nottingham, 2002. http://eprints.nottingham.ac.uk/14281/.
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The Ruv ABC and RecBCD protein complexes together can collapse and repair arrested replication forks. With their help a fork structure can be re-established on which replication can be restarted. ruv and recB mutants are therefore quite sensitive to UV light. Their survival is greatly decreased in the absence of the signalling molecules (p)ppGpp and increased when excess (p)ppGpp is present. (p)ppGpp are the effector molecules of the stringent response, regulating adaptation to starvation and other stressful environmental changes. Absence of (p)ppGpp can be compensated for by mutations in RNA polymerase that are called stringent mutations. Some of those, called rpo *, also - like excess (p)ppGpp - increase the survival of UV irradiated ruv and recB cells. A model proposed by McGlynn and Lloyd (Cell, Vol. 101, pp35-45, March 31, 2000) suggests that this is achieved by modulation of RNA polymerase, which decreases the incidence of replication fork blocks. In this work twenty-seven rpo * mutants were isolated, sequenced and mapped on the 3D structure of Thermus aquatic us RNA polymerase. I have found mutants in the ~ and ~' subunits of RNA polymerase. They lie mostly on the inner surface of the protein, well placed to make contact with the DNA substrate or the RNA product. A large number of rifampicin resistant mutations among rpo* mutations is explained by an overlap between the so-called Rif pocket and the "rpo* pocket". rpo * mutations, like stringent mutations, lead to a decrease in cell size, suppress filamentation and increase viability. For in vitro studies I purified wild type and two mutant RNA polymerases with help of a his-tagged a subunit. The experiments confirmed that rpo* mutant RNA polymerases form less stable open complexes than wild type, just like previously investigated stringent RNA polymerases. In addition I have shown here that (p)ppGpp leads to the destabilisation of RNA polymerase complexes stalled by nucleotide starvation or UV-induced lesions, though there is as yet no indication that rpo * mutations act in the same way.
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Meddows, Tom Richard. "DNA breakage and repair in Escherichia coli." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250525.
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Rogers, S. D. "DNA repair and mutagenesis in Penicillium chrysogenum." Thesis, University of Westminster, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233044.
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Blance, Stephen J. "DNA repair and recombination in Streptomyces coelicolor." Thesis, University of Liverpool, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367139.
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Smith, Colin. "DNA repair and replication in Streptomyces coelicolor." Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329440.
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Kumar, Ambika. "DNA interstrand crosslink repair in Trypanosoma brucei." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/36675.
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Genomes are constantly challenged by agents that promote DNA damage, with interstrand crosslinks (ICLs) representing a particularly dangerous lesion. Ongoing work in the Wilkinson laboratory aimed at identifying novel agents that target Trypanosoma brucei, the causative agent of African trypanosomiasis, identified several prodrugs that once activated form ICLs in this protozoan parasite. To understand the complexity of ICL repair systems that T. brucei employs to resolve such damage, a variety of null mutant lines were generated that lack activities postulated to fix such lesions. Phenotypic screens using various DNA damaging agents revealed that TbMRE11, TbEXO1, TbCSB, TbCHL1, TbFAN1, TbBRCA2 and TbRAD51 all help to resolve ICLs, implicating components of the homologous recombination, nucleotide excision repair and mismatch repair pathways in resolving this form of damage: This approach demonstrated that components of the translesion synthesis pathway (TbREV2 and TbREV3) do not play a significant role in ICL repair. In many organisms, nucleases belonging to the SNM1/PSO2 family play a key and specific role in the repair of ICLs with this property extending to the T. brucei homologue, TbSNM1. To assess whether there is a functional linkage between the DNA repair factors noted above and TbSNM1, a series of double null mutants were constructed and the susceptibility of these lines to ICL inducing agents determined. Identification of their epistatic/non-epistatic interactions revealed that T. brucei expresses at least two ICL repair systems with one pathway involving the concerted activities of TbSNM1/TbCSB/TbEXO1, that we postulate functions to repair ICLs encountered by the transcriptional machinery, while the other is centred upon TbMRE11/TbFAN1/TbEXO1 that may help resolve lesions which cause stalling of DNA replication forks. By unravelling how T. brucei repairs ICLs, specific inhibitors against key components of these pathways could be developed and used in combination with DNA damaging agents to target trypanosomal infections.
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Walker, Callum. "C9orf72 expansions disrupt ATM-mediated DNA repair." Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/20484/.
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Peacock, M. O. "UVA photosensitisers, protein oxidation and DNA repair." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1437625/.
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Pharmaceuticals can interact with sunlight to cause skin photosensitization and increase skin cancer risk. Interaction of drug molecules with solar UVA or visible radiation results in electronically excited states that damage biomolecules directly or indirectly via the formation of reactive species (RS). RS cause damage to DNA and its precursors, as well as to proteins and lipids. I have devised methods to examine the induction of oxidative protein damage in cultured human cells and used these to investigate the effects of UVA-activated photosensitizing drugs on the formation of protein carbonyls and the oxidation of protein thiol groups. I examined the effects of 6-thioguanine (6-TG) (a surrogate for azathioprine, an immunosuppressant), fluoroquinolone antibiotics, and the malignant melanoma therapeutic vemurafenib, each of which is associated with clinical skin photosensitivity and increased skin cancer risk in patients. All of these drugs are shown to be synergistically cytotoxic with UVA in cultured human cells and toxicity is concurrent with the generation of RS. I identify singlet oxygen as a major component of these photochemically-generated RS and show that widespread protein oxidation is caused. The Ku DNA repair heterodimer is identified as one of several targets for oxidation damage and I show using biochemical assays that damage to Ku compromises its function in the repair of DNA strand breaks. UVA irradiation of cells treated with the photosensitisers significantly compromises the removal of potentially mutagenic DNA lesions by the nucleotide excision repair pathway. Since this DNA repair pathway removes sunlight-induced DNA lesions and is the major protection against skin cancer, my findings have implications for the increased skin cancer risk associated with azathioprine. The ability of structurally dissimilar drugs to recapitulate the effects of 6-TG suggests that the observations may share a common mechanism.
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Bennett, Gwendolyn M. "Chromatin Regulators and DNA Repair: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/742.
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DNA double-strand break (DSB) repair is essential for maintenance of genome stability. However, the compaction of the eukaryotic genome into chromatin creates an inherent barrier to any DNA-mediated event, such as during DNA repair. This demands that there be mechanisms to modify the chromatin structure and thus access DNA. Recent work has implicated a host of chromatin regulators in the DNA damage response and several functional roles have been defined. Yet the mechanisms that control their recruitment to DNA lesions, and their relationship with concurrent histone modifications, remain unclear. We find that efficient DSB recruitment of many yeast chromatin regulators is cell-cycle dependent. Furthering this, we find recruitment of the INO80, SWR-C, NuA4, SWI/SNF, and RSC enzymes is inhibited by the non-homologous end joining machinery, and that their recruitment is controlled by early steps of homologous recombination. Strikingly, we find no significant role for H2A.X phosphorylation (γH2AX) in the recruitment of chromatin regulators, but rather that their recruitment coincides with reduced levels of γH2AX. We go on to determine the chromatin remodeling enzyme Fun30 functions in histone dynamics surround a DSB, but does not significantly affect γH2AX dynamics. Additionally, we describe a conserved functional interaction among the chromatin remodeling enzyme, SWI/SNF, the NuA4 and Gcn5 histone acetyltransferases, and phosphorylation of histone H2A.X. Specifically, we find that the NuA4 and Gcn5 enzymes are both required for the robust recruitment of SWI/SNF to a DSB, which in turn promotes the phosphorylation of H2A.X.
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Abratt, Valerie Rose. "DNA repair in Bacteroides fragilis Bf-2." Doctoral thesis, University of Cape Town, 1987. http://hdl.handle.net/11427/21823.
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Bibliography:pages 157-175.Repair deficient mutants of Bacteroides fragilis have been isolated in order to study the responses of this organism to various DNA damaging agents at the physiological and molecular levels. Two types of mutants were isolated by ethyl methane sulphonate mutagenesis of B.fragilis followed by selection for sensitivity to mitomycin C. One mutant (UVS9) showed sensitivity to both mitomycin C and far-UV irradiation. The other (MTC25) was more sensitive to mitomycin C than UVS9, but showed wild-type resistance to UV radiation. Both mutant strains had wild-type resistance to methyl methane sulphonate.
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Ruiz, Alarcón Rafael. "Targeting DNA repair mechanisms in aggresive neuroblastoma." Thesis, Högskolan i Skövde, Institutionen för hälsovetenskaper, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-19821.
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Neuroblastoma is a tumour derived from cells of the nervous system and is the most common solid tumour in childhood. MYCN amplified and 11q-deleted neuroblastoma, two high-risk neuroblastoma were investigated in this study. RAD51 gene family includes six central genes for the dsDNA breaks repair by homologous recombination, which has been reported as important in varying types of cancer. The study aims to investigate if the dysregulation of this gene family could be involved in the unstable genome of 11q-deleted neuroblastoma, and to better understand the link between both high-risk tumours. The RAD51 family genes’ expression level was measured by RT-qPCR in samples of 11q-deleted and MYCN-amplified neuroblastoma that were treated with a UVC treatment and were recovered during varying hours. R2 database and DAVID were used to study the RAD51 family’s expression levels, associated event-free survivability, and altered pathways. RAD51 family is highly dysregulated in these tumours, four genes of six were found to be altered in high-risk neuroblastoma. Four of six genes presented altered expression levels in 11q-loss, and three of six in the MYCN-amplified case after the UVC treatment. The event-free survival probability analysis shown that the levels of expressions associated with high-risk neuroblastoma coincide with those that represent a poor life expectancy. Altered pathways were different in each type of tumour. 11q-deletion neuroblastoma’s pathways were associated with the nervous system development, and MYCN-amplified was related to the immune system. This study suggests that 11q-loss neuroblastoma presents a greater RAD51 family dysregulation compared with MYCN-amplified one, which could explain why its genome is unstable.
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Bennett, Gwendolyn M. "Chromatin Regulators and DNA Repair: A Dissertation." eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/742.
Full textAbstract:
DNA double-strand break (DSB) repair is essential for maintenance of genome stability. However, the compaction of the eukaryotic genome into chromatin creates an inherent barrier to any DNA-mediated event, such as during DNA repair. This demands that there be mechanisms to modify the chromatin structure and thus access DNA. Recent work has implicated a host of chromatin regulators in the DNA damage response and several functional roles have been defined. Yet the mechanisms that control their recruitment to DNA lesions, and their relationship with concurrent histone modifications, remain unclear. We find that efficient DSB recruitment of many yeast chromatin regulators is cell-cycle dependent. Furthering this, we find recruitment of the INO80, SWR-C, NuA4, SWI/SNF, and RSC enzymes is inhibited by the non-homologous end joining machinery, and that their recruitment is controlled by early steps of homologous recombination. Strikingly, we find no significant role for H2A.X phosphorylation (γH2AX) in the recruitment of chromatin regulators, but rather that their recruitment coincides with reduced levels of γH2AX. We go on to determine the chromatin remodeling enzyme Fun30 functions in histone dynamics surround a DSB, but does not significantly affect γH2AX dynamics. Additionally, we describe a conserved functional interaction among the chromatin remodeling enzyme, SWI/SNF, the NuA4 and Gcn5 histone acetyltransferases, and phosphorylation of histone H2A.X. Specifically, we find that the NuA4 and Gcn5 enzymes are both required for the robust recruitment of SWI/SNF to a DSB, which in turn promotes the phosphorylation of H2A.X.
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Dogo, Federico. "MODELS OF DNA DAMAGE, REPAIR, AND MISREPAIR." Doctoral thesis, Università degli studi di Trieste, 2015. http://hdl.handle.net/10077/10889.
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2013/2014Within the range of the Virtual Biophysics Lab tumour growth numerical simulator, this work aims to develop a mathematical model able to describe the cell cycle desynchronization observed in the cell populations and the effects of DNA damage and repair due to ionizing radiation. Following a review of the already available models, some other original ones are proposed; one of these has been also tested on tumour cells by means of cytometry: the results of the related data analysis are not yet conclusive.
Nell'ambito del simulatore numerico di crescita tumorale Virtual Biophysics Lab, questo lavoro mira a sviluppare un modello matematico adatto a descrivere la desincronizzazione cellulare osservata nelle popolazioni cellulari e gli effetti del danno e riparazione del DNA indotti da radiazioni ionizzanti. A seguito di una recensione dei modelli già esistenti, ne vengono proposti alcuni altri originali; uno di questi è stato anche testato su cellule tumorali attraverso la citofluorimetria: i risultati della relativa analisi dati non sono ancora decisivi.
XXVII Ciclo
1983