Дисертації з теми "Transcription and repair"
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Chambers, Anna Louise. "Transcription termination by a transcription-repair coupling factor." Thesis, University of Bristol, 2005. http://hdl.handle.net/1983/b95a2024-73ae-460d-89bf-3c064a780c78.
Повний текст джерелаLainé, Jean-Philippe. "TFIIH and transcription coupled repair." Université Louis Pasteur (Strasbourg) (1971-2008), 2005. http://www.theses.fr/2005STR13195.
Повний текст джерелаAccurate coordination of the various events that maintain the integrity of the genome and regulate its expression is a prerequisite for differentiation, proliferation and cell life. The interconnection of such cellular processes is highlighted by the multi-functional complex TFIIH. Originally identified as a RNA polymerase II transcription factor, TFIIH also participates in the DNA nucleotide excision repair (NER) reaction. Ve focused my work on the functional/structural contribution within the complex of p52, one of the ten subunits of TFIIH, the link between transcription and NER, and the role of TFIIH in both. I first demonstrated that the carboxy-terminal of p52 is important for stabilizing the anchoring of XPB, another subunit of TFIIH, within the complex. This interaction is important for the role of XPB in the DNA opening step during transcription initiation. Then I focused my attention on the mechanism linking transcription to NER. I was able to show that a stalled elongating RNA polymerase II is able to recruit the repair factors at the site of the lesion and promote the removal of the DNA patch containing the lesion
Kim, Young-In Timothy. "Determinants of bacterial transcription-coupled repair." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521101.
Повний текст джерелаTrautinger, Brigitte W. "Interplay between DNA replication, transcription and repair." Thesis, University of Nottingham, 2002. http://eprints.nottingham.ac.uk/14281/.
Повний текст джерелаFan, Jun. "Single-molecule basis of transcription-coupled DNA repair." Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC213.
Повний текст джерелаThe DNA in living cells is constantly threatened by damages from both endogenous and exogenous agents, which can threaten genomic integrity, block processes of replication, transcription and translation and have also genotoxic effects. In response to the DNA damage challenge, organisms have evolved diverse surveillance mechanisms to coordinate DNA repair and cell-cycle progression. Multiple DNA repair mechanisms, discovered in both prokaryotic and eukaryotic organisms, bear the responsibility of maintaining genomic integrity; these mechanisms include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and double strand break repair (DSBR). Transcription-coupled DNA repair (TCR) is a specialized NER subpathway characterized by enhanced repair of the template strand of actively transcribed genes as compared to the classical global genome repair (GGR) subpathway of NER which does not distinguish between template and non-template strands. TCR achieves specialization via the involvement of RNA polymerase (RNAP) and the Mfd (Mutation Frequency Decline) protein, also known as TRCF (transcription repair coupling factor). TCR repair initiates when RNAP stalls at a DNA lesion on the transcribed strand and serves as the da mage sensor. The stalled RNAP must be displaced so as to make the lesion accessible to downstream repair components. E. Coli Mfd translocase participates in this process by displacing stalled RNAP from the lesion and then coordinating assembly of the UvrAB(C) components at th( damage site. Recent studies have shown that after binding to and displacing stalled RNAP, Mfd remains on the DNA in the form of a stable, translocating complex with evicted RNAP. So as to understand how UvrAB(C) are recruited via the Mfd-RNAP complex, magnetic trapping of individual, damaged DNA molecules was employed to observe-in real-time this multi¬component, multi-step reaction, up to and including the DNA incision reaction by UvrC. It was found that the recruitment of UvrA and UvrAB to the Mfd-RNAP complex halts the translocating complex and then causes dissolution of the complex in a molecular "hand-off" with slow kinetics Correlative single-molecule nanomanipulation and fluorescence further show that dissolution of the complex leads to loss of not only RNAP but also Mfd. Hand-off then allows for enhanced incision of damaged DNA by the UvrC component as compared to the equivalent single-moleculE GGR incision reaction. A global model integrating TCR and GGR components in repair was proposed, with the overall timescales for the parallel reactions provided
Malik, Shivani. "REGULATORY MECHANISMS OF TRANSCRIPTION AND ASSOCIATED DNA REPAIR." OpenSIUC, 2012. https://opensiuc.lib.siu.edu/dissertations/626.
Повний текст джерелаCerutti, Elena. "Nucleotide Excision Repair at the crossroad with transcription." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1057.
Повний текст джерелаThe integrity of DNA is continuously challenged by a variety of endogenous and exogenous agents (e.g. ultraviolet light, cigarette smoke, environmental pollution, oxidative damage, etc.) that cause DNA lesions which interfere with proper cellular functions. Nucleotide Excision Repair (NER) mechanism removes helix-distorting DNA adducts such as UV-induced lesions and it exists in two distinct sub-pathways depending where DNA lesions are located within the genome. One of these sub pathways is directly linked to the DNA transcription by RNA Polymerase 2 (TCR). In the first part of this work, we demonstrated that a fully proficient NER mechanism is also necessary for repair of ribosomal DNA, transcribed by RNA polymerase 1 and accounting for the 60 % of the total cellular transcription. Furthermore, we identified and clarified the mechanism of two proteins responsible for the UV-dependent nucleolar repositioning of RNAP1 and rDNA observed during repair. In the second part of this work, we studied the molecular function of the XAB2 protein during NER repair and we demonstrated its involvement in the TCR process. In addition, we also shown the presence of XAB2 in a pre-mRNA splicing complex. Finally, we described the impact of XAB2 on RNAP2 mobility during the first steps of TCR repair, thus suggesting a role of XAB2 in the lesion recognition process
MacKinnon-Roy, Christine. "The role of transcription elongation factor IIS in transcription-coupled nucleotide excision repair." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28454.
Повний текст джерелаAbdullah, Mohamad Faiz Foong. "Transcription factors and mismatch repair proteins in meiotic recombination." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249637.
Повний текст джерелаRiedl, Thilo. "Tfiih : A factor between DNA repair and transcriptional activation." Université Louis Pasteur (Strasbourg) (1971-2008), 2003. http://www.theses.fr/2003STR13059.
Повний текст джерелаHaines, Nia. "Damage detection during transcription coupled DNA repair in Escherichia coli." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.690774.
Повний текст джерелаSen, Rwik. "REGULATION OF EUKARYOTIC TRANSCRIPTIONAL ELONGATION AND ASSOCIATED DNA REPAIR." OpenSIUC, 2016. https://opensiuc.lib.siu.edu/dissertations/1205.
Повний текст джерелаLópez, de Heredia Luis. "Analysis of the C/EBP family of transcription factors in neuronal repair." Thesis, Queen Mary, University of London, 2009. http://qmro.qmul.ac.uk/xmlui/handle/123456789/545.
Повний текст джерелаHill, Sarah J. "Familial ALS Proteins Function in Prevention/repair of Transcription-Associated DNA Damage." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:27007760.
Повний текст джерелаShotton, Priyasri. "A STUDY OF THE INTERPLAY BETWEEN SACCHAROMYCES CEREVISIAE TRANSCRIPTION AND DNA REPAIR." OpenSIUC, 2012. https://opensiuc.lib.siu.edu/dissertations/552.
Повний текст джерелаGottlieb, Tanya M. "Biochemical characterisation and functional analysis of the DNA-dependent protein kinase." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338306.
Повний текст джерелаFeuerhahn, Sascha. "Mechanistic insights into the effect of oxidative lesions and anticancer drugs on RNA pol II transcription and transcription coupled repair." Université Louis Pasteur (Strasbourg) (1971-2008), 2008. https://publication-theses.unistra.fr/restreint/theses_doctorat/2008/FEUERHAHN_Sascha_2008.pdf.
Повний текст джерелаThe vital process of gene expression by RNA polymerase II (RNA pol II) can be disturbed by DNA lesions. A stalled RNA pol II can trigger transcription coupled repair (TCR). A central player during TCR is the Cockayne syndrome group B protein (CSB), which, when mutated, can give rise to Cockayne syndrome (CS). In this thesis, the effect of three abundant oxidative lesions was investigated using a well defined in vitro transcription system. Oxidative lesions blocked RNA pol II progression to a lesion-specific extent. Importantly, the presence of nuclear extract alleviated this block, and the subsequent purification of this bypass activity from HeLa nuclear extract identified a role for the elongation factor TFIIF in RNA pol II translesion RNA synthesis. Other elongation factors, including CSB, were identified to promote bypass of oxidative DNA damage for a factor-specific subset of lesions, which could have implications for CS. Secondly, the poorly understood mechanism of the novel anticancer alkylating agent Trabectedin, which is more potent in cells proficient in TCR, was investigated in this thesis. It was found that Trabectedin can lead to a persisting TCR complex by the inhibition of the endonuclase cut of XPG and the stimulation of XPF-ERCC1 cutting during TCR. A related cancer therapeutic is Zalypsis. In this thesis, this compound was shown to efficiently inhibit early steps in transcription. Which could have important implications for breast or prostate cancer
Taschner, M. J. "Transcription-coupled nucleotide excision repair and its regulation by the DNA damage checkpoint." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18946/.
Повний текст джерелаGopaul, Diyavarshini. "Study of the molecular mechanisms linking transcription and DNA repair in Saccharomyces cerevisiae." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS347.
Повний текст джерелаNucleotide excision repair (NER) is a well conserved pathway that removes helix-distorting DNA lesions such as those arising upon UV irradiation. Global genome repair subpathway (GG-NER) removes the DNA lesions in the genome overall, and transcription-coupled repair (TC-NER) removes the DNA lesions interfering with Pol II progression through actively-transcribed regions. Defects in the NER pathway may lead to severe human pathologies. For instance, mutations in human XPG gene, encoding a 3’ endonuclease essential for NER, give rise to xeroderma pigmentosum (XP) sometimes associated with Cockayne syndrome (CS). Recently, the laboratory discovered a functional link between Rad2/XPG and Mediator in Saccharomyces cerevisiae (Eyboulet et al., 2013). Mediator is a large multisubunit complex essential for transcription regulation. We suggest that Mediator is involved in TC-NER by facilitating Rad2 recruitment to transcribed genes.My PhD work aimed at addressing the molecular mechanisms of this link between transcription and DNA repair, especially by investigating the functional interplay between Mediator and the NER machinery in yeast Saccharomyces cerevisiae.RNA Pol II is the first complex of TC-NER that encounters the DNA damage. Moreover, both Mediator and Rad2/XPG interact with Pol II. However, a functional interplay between all these components related to TC-NER remained to be determined. Using genetic and genomic approaches, in particular ChIP-sequencing in TFIIH (kin28), RNA Pol II (rpb9) and Mediator (med17) mutants, our work led us to propose a model where Rad2 shuttles between Mediator on upstream activating sequence (UAS) and RNA Pol II on transcribed regions (Georges, Gopaul et al., under review). Our results also suggest that Mediator functions in transcription and DNA repair are closely related.Moreover, we showed that Mediator’s link to NER can be extended to other NER proteins. Indeed, we identified a physical interaction between Mediator and other NER proteins, including Rad1/XPF, Rad10/ERCC1 and Rad26/CSB in the absence of UV irradiation. Similarly to Rad2, we demonstrated that Rad1 and Rad10 do not have a major role in yeast transcription. To further study the functional link between Mediator and the NER machinery, we obtained the genomic distribution of different NER proteins by ChIP-sequencing. We found that some promoter regions are co-occupied by Mediator and these NER proteins, and that relationships between Mediator and these NER proteins are more complex than between Mediator and Rad2. We also investigated if physical interactions between Mediator and NER proteins are modified after UV, we did not observe any significant change. Furthermore, we observed that the chromatin binding profiles of NER proteins and Mediator are modified after UV-irradiation. ChIP-sequencing will be carried out to get a genome-wide view of their chromatin binding profiles.In conclusion, we have strengthened the link between Rad2/XPG, Mediator and RNA Pol II, providing mechanistic insights into functional interplay between these components related to transcription-coupled repair, and showed that the link between Mediator and the NER machinery can be extended to other proteins. Taken together, our results suggest a close relation between Mediator functions in transcription and in NER, two fundamental processes dysfunction of which leads to human diseases
Tamburini, Beth Ann. "Characterization of chromatin dynamics during DNA repair and transcriptional regulation /." Connect to full text via ProQuest. IP filtered, 2006.
Знайти повний текст джерелаTypescript. Includes bibliographical references (leaves 137-151). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
Mello, Jill Ann 1966. "Transcription and mismatch repair in the mechanism of action of the anticancer drug cisplatin." Thesis, Massachusetts Institute of Technology, 1997. http://hdl.handle.net/1721.1/42993.
Повний текст джерелаVita.
Includes bibliographical references (leaves 188-212).
cis-Diamminedichloroplatinum(II) (cis-DDP or cisplatin) is a powerful cytotoxin and anticancer therapeutic, used most effectively in the treatment of testicular and ovarian cancers. By contrast, the geometric isomer of cisplatin, trans- DDP, is comparatively non-toxic and fails to show significant antitumor activity. Cisplatin is believed to derive its cytotoxic effects from processes triggered by its reaction with DNA. The formation of cisplatin adducts can elicit many cellular responses, including inhibition of both DNA replication and transcription. Cisplatin DNA adducts are also specifically recognized by various proteins within the cell, and such cisplatin-damage recognition proteins have been previously suggested to play a role in the clinical efficacy of the drug. To date, however, the precise mechanism by which cisplatin lesions mediate the cytotoxic and antitumor activities of cisplatin remains elusive. The work in this dissertation evaluated two possible mechanisms by which cisplatin might exert its cytotoxic effects that had been heretofore largely unexplored. The first aspect of this work evaluated a model wherein the differential cytotoxic and antitumor activities of cisplatin and trans-DDP may result from a greater ability of cisplatin DNA damage to inhibit RNA transcription. A nonreplicating plasmid harboring the [beta]-galactosidase ([beta]-gal) reporter gene was modified in vitro with either of the two platinum compounds and transfected into human or hamster cell lines. The use of cell lines both proficient and deficient in nucleotide excision repair allowed the examination of transcriptional bypass independent of excision repair for each platinum compound. A two to three fold higher level of transcription was observed in both cell lines from plasmids containing trans-DDP adducts as compared to plasmids modified by cis-DDP. This difference in transcriptional activity was not decreased in human and rodent nucleotide excision repair deficient cell lines, indicating that more efficient excision repair of the trans- DDP adducts was not the cause of its lower ability to block transcription. The possibility that trans-DDP lesions are preferentially bypassed by RNA polymerase was examined by monitoring the elongation of [beta]-gal mRNA on damaged templates in vivo. Nascent [beta]-gal mRNA transcripts were recovered from nucleotide excision repair deficient xeroderma pigmentosum A cells transfected with platinated plasmids, and the extent of RNA synthesis was measured by using ribonuclease protection. The results showed that four-fold more trans-DDP than cis-DDP adducts were required to inhibit transcription elongation by 63 %. RNA polymerase II translocated past a single, representative DNA adduct of cisplatin and trans-DDP in vivo with an efficiency of 0- 16% and 60-76%, respectively. These data support the view that inhibition of transcription may contribute to the greater cytotoxicity of cis-DDP compared with its trans isomer. The second aspect of this work evaluated a possible novel role of the human mismatch repair protein, hMSH2, as a cisplatin-damage recognition protein. The interaction of purified recombinant hMSH2 with DNA containing adducts of cisplatin and various cisplatin analogs was examined in vitro by using an electrophoretic gel mobility shift assay. The results showed that hMSH2 recognizes and binds specifically to DNA adducts of cisplatin. This protein displayed affinity for DNA modified by therapeutically effective platinum complexes, but not for that modified by clinically inactive platinum compounds such as trans-DDP. Recognition by hMSH2 was dictated, in part, by the major intrastrand DNA adduct formed by cisplatin. The results also show that hMSH2 is overexpressed in testicular and ovarian tissue, tissues in which tumors are best treated by cisplatin. These results complement a growing body of literature correlating mismatch repair activity with cisplatin toxicity in Escherichia coli and mammalian cells. Viewed together, these observations are consistent with a model whereby mismatch repair plays an active role in potentiating cisplatin DNA lesion toxicity. Further, these results may provide insight into a previously undiscovered mechanism by which tumor cells may acquire resistance to CISplatin.
by Jill Ann Mello.
Ph.D.
Liu, Hairong. "DNA repair and transcription of the yeast MFA2 gene : roles of Tup1p, Gcn5p and Rad16p." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/54096/.
Повний текст джерелаOksenych, Valentyn. "Molecular mechanisms of recruitment of transcription/repair factor TFIIH to the sites of damaged DNA." Strasbourg, 2009. https://publication-theses.unistra.fr/public/theses_doctorat/2009/OKSENYCH_Valentyn_2009.pdf.
Повний текст джерелаYang, Margaret Hwae-Ling. "Mutations flanking the DNA channel through RNA polymerase II affect transcription-coupled repair in Saccharomyces cerevisiae /." view abstract or download file of text, 2007. http://proquest.umi.com/pqdweb?did=1417800941&sid=1&Fmt=2&clientId=11238&RQT=309&VName=PQD.
Повний текст джерелаTypescript. Includes vita and abstract. Includes bibliographical references (leaves 80-87). Also available for download via the World Wide Web; free to University of Oregon users.
O'Connell, Charlotte. "Roles of histone deacetylases and histone phosphorylation in transcription and nucleotide excision repair in Saccharomyces cerevisiae." Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/54298/.
Повний текст джерелаRuff, C. A. D. B. "The role of growth associated transcription factors c-Jun and ATMIN in neuronal regeneration and repair." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19813/.
Повний текст джерелаAssenmacher, Nora. "Structural and biochemical analysis of the UvrA binding module of the bacterial transcription repair coupling factor Mfd." [S.l.] : [s.n.], 2006. http://edoc.ub.uni-muenchen.de/archive/00006371.
Повний текст джерелаAßenmacher, Nora. "Structural and biochemical analysis of the UvrA binding module of the bacterial transcription repair coupling factor Mfd." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-63719.
Повний текст джерелаBollins, Jack Michael. "The non-canonical roles of the transcription-repair coupling factor, Mfd, in Escherichia coli and Campylobacter jejuni." Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738545.
Повний текст джерелаLee, Sungkeun. "Molecular genetic analysis of nucleotide excision repair genes in Dictyostelium discoideum /." free to MU campus, to others for purchase, 1997. http://wwwlib.umi.com/cr/mo/fullcit?p9841209.
Повний текст джерелаTraboulsi, Hussein. "Relationship between the transcription/DNA repair factor TFIIH and the Peroxisome Proliferator-Activated Receptor coactivator 1α PGC-1α". Strasbourg, 2011. http://www.theses.fr/2011STRA6063.
Повний текст джерелаMutations in the subunit XPD of the transcription factor IIH (TFIIH) lead to genetic disorders including trichothiodystrophy TTD. Knowing that subunit MAT1 of TFIIH is required for the full function of the proliferator activated receptor γ coactivator 1 α (PGC-1α), we decided to study the influence of the mutation R722W in XPD on PGC-1α activity. Using immortalized hepatocytes isolated from TTD mutant mice, we investigated the expression of PGC-1α target genes involved in gluconeogenesis. We observed that these genes are downregulated in TTD hepatocytes. Moreover, we found that XPD mutation disrupted the interaction between PGC-1α and the deacetylase Sirtuin1 (SIRT1) leading to reduced activation of PGC-1α. We also showed that PGC-1α and SIRT1 both interact with TFIIH. We thus established that TFIIH is required for full PGC-1α activity in the gluconeogenesis pathway, and more likely through modulation of SIRT1 activity. Therefore, our results suggest that the deregulation in TTD likely results from the inability of the mutated TFIIH to fully participate in recruitment of PGC-1α and/or SIRT1 to the DNA
Phillips, Jennifer Elizabeth. "Runx2-Genetically Engineered Dermal Fibroblasts for Orthopaedic Tissue Repair." Diss., Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/19818.
Повний текст джерелаIltis, Izarn. "Rôles transcriptionnels des facteurs NER." Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00849966.
Повний текст джерелаYu, Sung-Lim. "Analysis of the response of nucleotide excision repair genes in Dictyostelium discoideum /." free to MU campus, to others for purchase, 1997. http://wwwlib.umi.com/cr/mo/fullcit?p9841196.
Повний текст джерелаHardy, Robert George. "Alterations in cadherin and catenin expression in colonic neoplasia, injury and repair : regulation of P-cadherin transcription in the colon." Thesis, University of Birmingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396450.
Повний текст джерелаBourseguin, Julie. "Etude des relations biochimiques, moléculaires et fonctionnelles entre le facteur de transcription MiTF et la voie de réparation FANC." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS271.
Повний текст джерелаProteins and pathways involved in DNA damage response (DDR), maintaining genetic stability and safeguarding DNA replication, act not only as caretakers against cancer initiation but also play a major role in sustaining cancer progression and resistance to pharmacological-based therapies. The FANC pathway is central in maintaining genetic stability under conditions of replication stress and its loss-of-function is causative of the cancer predisposition and chromosome fragility syndrome Fanconi Anemia (FA).We demonstrate here that FANC proteins are over-expressed and over-activated in metastatic melanoma cells expressing the oncogenic microphthalmia-associated transcription factor (MiTF), which high expression is maintained in 80% of melanoma cases. We identified MiTF as a critical regulator of the expression of the mRNAs coding key proteins of the FANC pathway in melanoma cells and demonstrated that MiTF-silenced cells display the primary characteristics of FA cells, i.e., the cellular and chromosomal hypersensitivity to DNA interstrand crosslink- inducing agents. Moreover, FANC pathway also modulates melanoma cell migration. Our observations point to a central role of the FANC pathway in cellular and chromosomal resistance to DNA damage in melanoma cells. Thus, the FANC pathway appears as a promising new therapeutic target for melanoma treatment.Inversely, we observed that FANC pathway loss-of-function is associated to increased expression of MiTF in both FA patient-derived and siRNA-downregulated cells. We demonstrated that the FANC pathway negatively regulates MiTF expression at the mRNA level and have obtained preliminary data suggesting that FANCD2 associates to the MiTF promoter, impeding the action of the NF-kB transcription factor. MiTF depletion increases MMC sensitivity in FANC pathway proficient cells, but does not modify the sensitivity of FA cells, supporting the hypothesis that MiTF acts on the DDR by regulating the expression of FANC proteins. Finally, we demonstrated that MiTF expression is induced in response to inflammatory stimuli, like TNF-a. Thus, altered MiTF expression in FA could be involved in the pigmentation defects and microphthalmia reported in patients.In conclusion, we will present a corpus of both validated and yet preliminary data that strongly supports the existence of an epistatic relationship between MiTF and the FANC pathway. This circuitry appears to have an important role in melanoma resistance to chemotherapies and in some FA pathological traits
Richards, Jodi D. "Helicases and DNA dependent ATPases of Sulfolobus solfataricus." Thesis, University of St Andrews, 2008. http://hdl.handle.net/10023/474.
Повний текст джерелаVesin, Rose-Marie. "Etude du rôle du facteur de transcription Helios dans les cellules souches hématopoïétiques." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ117/document.
Повний текст джерелаHematopoietic stem cells (HSCs) give rise to all blood cell lineages but the mechanisms responsible of HSCs responses to stress remain partially understood. I studied the role of the transcription factor Helios in HSCs, where Helios is highly and specifically expressed. I found that HSCs from young Helios null mice (He-/-) reconstitute the hematopoietic system of irradiated recipient mice similarly to HSCs from WT mice in primary transplantations, but out-perform WT cells in secondary and tertiary transplantations. Strikingly, HSCs from 2-year-old He-/- mice had 8-fold higher reconstitution potential than old WT HSCs in primary transplantations. Moreover, the pool of long-term HSCs in old He-/- mice resembles that of young WT animals in both phenotype and frequency. HSCs from old He-/- mice present a down regulation of genes involved in aging. Further, young He-/- HSCs express reduced mRNA levels of genes encoding DNA repair proteins as well as those associated with thep53 pathway. When He-/- and WT HSCs were subjected to DNA damage by different agents like neocarzinostatin, camptothecin, or etoposide, DNA damage-induced apoptosis, senescence and cell cycle arrest were significantly impaired in He-/- HSCs. This phenotype was accompanied by a poor induction of p53 target genes and impaired clearance of gammaH2AX foci. Furthermore, I found that Helios synergies with p53 to regulate the DNA damage responses of HSCs. My results suggest that,in synergy with p53, Helios controls HSC aging by preventing the accumulation of DNA damage in these cells
Eyboulet, Fanny. "Mécanismes de l'activation de la transcription in vivo par le Médiateur." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112177/document.
Повний текст джерелаIn eukaryotes, the synthesis of messenger RNA (mRNA) is highly regulated in response to the binding of specific activators to regulatory regions. This step allows the recruitment of coactivators, general transcription factors (GTFs) and RNA polymerase II (Pol II) to form the preinitiation complex (PIC). Mediator is a co-activator complex essential to this process and although it has been studied intensively during the last few years, its complexity has precluded a detailed understanding of the molecular mechanisms of its function in vivo. During my PhD, I focused on the Med17 subunit which plays a central role within the Mediator head module and interacts directly with Pol II. We obtained a large collection of temperature-sensitive mutants of this subunit in the yeast Saccharomyces cerevisiae, and then characterized these mutants by different molecular biology and functional genomics approaches. Our ChIP-seq analyses show that Mediator influences independently the recruitment and/or the stabilization of TBP as well as TFIIH core and kinase modules on the genome. These results indicate that, unlike a linear sequence observed in vitro, in vivo the PIC assembly is a non-sequential multistep process and that Mediator is important to orchestrate the recruitment of different PIC components. Furthermore, we identified a direct contact between Mediator and Rad2/XPG, an endonuclease involved in DNA repair. A genome-wide analysis reveals that this protein is present on class II genes in the absence of genotoxic stress, and that its genomic localization correlates with that of Mediator. We thus demonstrated that Mediator is important for Rad2 recruitment, suggesting a new role for this complex in DNA repair, in addition to its co-activator role in Pol II transcription
Soret, Christine. "Mise en évidence d'une fonction non-transcriptionnelle du facteur de transcription homéotique Cdx2." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ109/document.
Повний текст джерелаColorectal cancer is the 2nd cause of mortality by cancer in industrialized countries. New treatments allowing to prevent the evolution of the disease are needed. It is important to better understand the actors implicated in carcinogenesis. During cancer development, tumor suppressor genes are inhibited and oncogenes are activated, thus disrupting the homeostasis of the tissue and transforming the cells. During my thesis, I have been interested in two genes having two opposite functions in CCR : Cdx2 is a tumor suppressor while Hoxb7 acts as an oncogene. My work allows to highlight (i) a new non-transcriptional function of Cdx2 : inhibitor of the reparation of DNA breaks specifically in the colon, (ii) and that the expression level of Cdx2 and Hoxb7 genes inside the tumor can have an importance in the choice of the CCR treatment
Semer, Maryssa. "Le facteur de réparation XPC est un cofacteur de l'ARN polymérase II régulant les modifications post-traductionnelles des histones lors de la transcription." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ040/document.
Повний текст джерелаNER involves a cascade of protein complexes including the DNA damage sensor (XPC/HR23B). Mutations in NER genes (TTD-A, XPA-G, XPV, CSA and CSB) are associated with human genetic diseases including Xeroderma pigmentosum (XP), Trichothiodystrophy (TTD) and Cockayne Syndrome (CS). All the symptoms can only be explained by a defect of the DNA repair. However all the symptoms can only be explained by a defect of the DNA repair. However, it has been proven that NER factors are also involved in transcription. As the genomic scale to better understand the consequences of its deregulation in a pathological context. In this sense, my second goal has been to characterize at the molecular level the etiology of new XP patients by analyzing in a combined way the molecular events of the NER and the transcription associated with XPC. Our different experimental approaches have made it possible to identify at genomic level a set of gene whose promoters are regulated both positively and negatively by XPC in a dependent RAR context. In addition, we show that XPC interacts with KAT2A contained in the ATAC complex, as well as with the transcription factor E2F1, the chromatin remodeling factor BRD2, and the histone variant H2A.Z. Via KAT2A, this complex will acetylate not only H2A.Z but also H3K9 at promoters targeted by E2F1
Palassin, Pascale. "Etude du rôle du corégulateur transcriptionnel RIP140 dans le contrôle de l'instabilité microsatellitaire des cancers colorectaux héréditaires." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT054/document.
Повний текст джерелаThe transcriptional coregulator RIP140 is an ubiquitous cofactor playing a major role in the regulation of many physiopathological processes. It can either act as a coactivator or as a corepressor of signaling pathways depending on its recruitment on target genes. It has been shown that RIP140 is a good prognostic marker in sporadic intestinal tumorigenesis. This work focuses on its role in familial colorectal cancers and particularly in relation to the Lynch syndrome (LS). Lynch syndrome is a hereditary cancer predisposition, mostly colorectal, characterized by a defect in the Mismatch Repair (MMR) system, due to a first germline mutation of one gene of this system. Loss of MMR function induces a microsatellite instability (MSI) phenotype. However, there are some MSI familial colorectal cancers, where neither germinal nor somatic alteration of one MMR gene is found. They are referred to as Lynch like Syndrome (LLS) and their overall management is identical to that of LS. Murine models and colorectal cell lines, harboring modulations of RIP140 expression, allowed us to demonstrate the positive transcriptional regulation of the MMR genes, MSH2 and MSH6 by RIP140. Functional validation of this regulation was explored by microsatellite instability and sensitivity to various cytotoxic drugs analyses. A positive correlation has been confirmed between RIP140 and MSH2 and MSH6 gene expression in a cohort of 396 patients. Moreover, the transcriptional regulation by RIP140 of a specialized translesional DNA polymerase, the Polκ polymerase, has been investigated. Polκ ensures microsatellite sequences replication. We have demonstrated that RIP140 positively stimulates the expression of the POLK gene in our cell models and which appears correlated with that of RIP140 in human colorectal tumors. Finally, by sequencing different cell lines, we found a frameshift mutation of RIP140, generating a truncated protein with loss of the last two repression domains. High-throughput sequencing allowed us to look for this mutation in patient MSI colorectal tumor samples. This mutation was found in 19% of these tumors, especially LLS (16,2%), where it has been associated with lower overall survival. This mutation affects the antiproliferative and transrepressive properties of RIP140, as well as the positive regulation of the MSH2, MSH6 and POLK gene. Development of a specific antibody for this mutation would be extremely useful in following the expression of this mutated form within tumors and first tests have been already carried out. In conclusion, RIP140 controls expression of major genes involved in genome integrity maintenance and a mutation of this transcriptional coregulator could be responsible for microsatellite instability of some tumors where alterations of MMR genes are not found. Clinical studies on larger cohorts will be necessary to validate its interest as a marker usable in patient management
Xie, Jenny X. "Regulation of BACH1/FANCJ Function in DNA Damage Repair: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/435.
Повний текст джерелаAli, Nsrein. "Rôle du facteur de transcription HIF-1α dans la physiologie cutanée et dans la réponse à l'exposition UV". Thesis, Vandoeuvre-les-Nancy, INPL, 2010. http://www.theses.fr/2010INPL041N/document.
Повний текст джерелаThe transcription factor HIF-1 is a heterodimer composed of an α and ß subunit. HIF-1 is capable of recognizing a consensus sequence called HRE (hypoxia Response Element) and regulate the expression of more than 200 target genes involved in various cellular mechanisms. We are interested in studying the role of HIF-1α in the skin physiology.Our results show that HIF-1α regulates the expression of two main factors (XPC and XPD) involved in nucleotide excision repair through binding on HRE in their promoter regions. Quantitative chromatin immunoprecipitation assays further revealed putative HREs in the genes encoding other DNA repair proteins (XPB, XPG, CSA and CSB), suggesting that HIF-1α is a key regulator of the DNA repair machinery. We proved that HIF-1α is essential for keratinocyte adhesion through its regulation exerted on laminin-332 and integrins (α6, ß1). The lack of HIF-1α expression also prevents the reconstruction of epidermis by human keratinocytes. Our results showed that mice constitutively depleted for HIF-1α in their epidermis develop with age a phenotype of inflammation in several regions. These mice are very sensitive to the stress resulting from wound injury and UVB irradiation. HIF-1α depletion in the epidermis of inducible mice using tamoxifen results in a detachment of the epidermis in suprabasal layers. These mice die within two weeks after injection of tamoxifen
Charles, Richard John Lalith. "FACT, réparation par excision de bases et fixation du facteur de transcription NF-kB sur la chromatine." Thesis, Grenoble, 2012. http://www.theses.fr/2012GRENV034/document.
Повний текст джерелаFACT is a vital protein which has multiple roles including one in transcription and repair of damaged DNA. However, how FACT assists repair and transcription remains elusive. In this work, we have first studied the role of FACT in Base Excision Repair (BER). We used nucleosomes containing DNA with randomly incorporated uracil. We found that the enzyme UDG is able to remove uracils facing the solution and not the uracils facing the histone octamer. The simultaneous presence of FACT and RSC (a chromatin remodeler involved in repair) allows, however, a very efficient removal of uracil facing the histone octamer by UDG. In addition, the concerted action of FACT and RSC permits the removal of the otherwise un-accessible oxidative lesion 8-oxoG from nucleosomal templates by OGG1. This was achieved thanks to the co-remodeling activity of FACT. Here we described for the first time this novel property of FACT and we show in a series of biochemical experiments that FACT is able to boost the remodeling activity of RSC. The experiments reveal that the presence of FACT increases the efficiency of RSC to transform the energy freed by ATP hydrolysis into “mechanical” work. The presented data suggest a stochastic nature of BER functioning in vivo, FACT being a key factor in the repair process. The implication of the co-remodeling activity of FACT in NF-kB factor binding to nucleosomal templates was also investigated. The generation of remodeled, but not mobilized nucleosomes (remosomes), was not sufficient to promote NF-kB binding. However, the RSC-induced nucleosome mobilization allows efficient NF-kB interaction with nucleosomal DNA. Our data are instrumental in deciphering the molecular mechanism of FACT implication in BER and NF-kB mediated transcription
Hillukkala, T. (Tomi). "Roles of DNA polymerase epsilon and TopBP1 in DNA replication and damage response." Doctoral thesis, University of Oulu, 2006. http://urn.fi/urn:isbn:9514282922.
Повний текст джерелаGuintini, Laetitia. "Étude de la réparation des lésions induites par les UVs dans les extrémités chromosomiques de la levure Saccharomyces cerevisiae." Thèse, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/9524.
Повний текст джерелаAbstract : Telomeric DNA is made of short tandem repeats located at the ends of chromosomes and their maintenance is critical to prevent genome instability. DNA lesions constitute a serious risk to genome integrity. Thus, DNA repair mechanisms are required for continuous and unabridged cell divisions. The nucleotide excision repair (NER) pathway removes bulky DNA lesions such as UV-induced photoproducts, like the cyclobutane pyrimidine dimers (CPD). NER is divided in two sub-pathways: global genome repair (GGR) and the faster transcription-coupled repair (TCR), which only differ in how they recognize UV-induced lesions. In eukaryotes, NER must find and repair DNA lesions that are buried in nucleosomes. In the yeast S. cerevisiae, genes positioned close to telomeres are silenced by a heterochromatin-like structure that is formed by silent information regulator proteins (Sir). To determine if nucleosomes and chromatin in subtelomeric regions affect the efficiency of NER, we studied the repair of photoproducts in different telomere-associated regions in both, WT and SIR genes deleted cells (sirΔ). We found that NER efficiency was modulated by the presence of nucleosomes on the subtelomeric type X element. In addition, in absence of Sir proteins, NER efficiency increased and was not modulated by nucleosomes, indicating that nucleosome positioning was less defined in sirΔ cells. Remarkably, in telomeric restriction fragment, NER was less efficient at telomeres than in the subtelomere type Y’ element. We suggest that low NER efficiency at the very end of chromosomes results from attachment sites to the nuclear periphery. Our data indicate that NER in sub-telomeric chromatin is modulated by Sir proteins stabilized-nucleosomes, and that NER is inhibited in telomeric chromatin by the presence of YKu, independently from the presence of Sir proteins. It was recently shown that the chromosome ends are transcribed and a non-coding RNA, called TERRA, is produced. Currently the precise functions of TERRA are not understood. Our second goal is to help understand the function of TERRA. We think that transcription at the chromosome ends could facilitate the removal of DNA lesions from heterochromatin by TCR, which would prevent the formation of mutations and, ultimately, chromosome shortening. Our data showed that TC-NER is effective in Y’ element and the telomere. Without Sir proteins, TERRA transcription is found in a particular region at the end of the X element. The transcription of TERRA could improve the repair of UV-induced lesions.
Khobta, Andriy [Verfasser]. "Consequences of DNA damage for gene transcription : direct effects of modified nucleobases and the role of base excision repair = Folgen von DNA-Schäden für die Gentranskription / Andriy Khobta." Mainz : Universitätsbibliothek Mainz, 2014. http://d-nb.info/1070334405/34.
Повний текст джерелаHochhauser, Daniel. "Transcriptional regulation of topoisomerase II." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333178.
Повний текст джерелаSenarisoy, Muge. "Etudes des fonctions du facteur de transcription YB-1, de l'ADN glycosylase hNTH1 et de la topoisomerase humaine I dans le contexte de la résistance aux drogues et en relation avec les voies de réparation de l'ADN." Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAV064/document.
Повний текст джерелаAcquired resistance to anti-cancer therapy is common and is a major clinical issue. Functional DNA repair pathways provide a common mechanism for drug resistance, but it can also result from mutations or reduced expression of the targeted protein. The overexpression or nuclear localisation of the multifunctional Y-box binding protein (YB-1) is considered as a prognostic marker for drug resistance in tumours. YB-1 has several interaction partners in cells; in this study, we have focused on its interaction with the human DNA repair enzyme NTH1 (hNTH1) and human DNA topoisomerase I (hTopoI), two enzymes that have been shown to be stimulated by YB-1. The abundance of the hNTH1/YB-1 complex was shown to increase in cisplatin-resistant tumour cells. Human TopoI is an essential enzyme involved in cellular regulation of DNA supercoiling and is the target of several anti-cancer agents. YB-1 enhances the activity of hTopoI and its sensitivity to hTopoI inhibitor, camptothecin in tumour cells. We have characterised the YB-1/hNTH1 and YB-1/hTopoI complexes in vitro and in vivo using Fluorescence Resonance Energy Transfer (FRET) measurements to identify and develop new strategies for the treatment of drug-resistant tumours. We also designed and optimised an original FRET-based biosensor to screen two medium-sized chemical libraries in order to find potential inhibitors of the hNTH1/YB-1 complex. Several “hits” were identified that significantly reduced the FRET level of our biosensor. For some of these compounds, we have reproduced these results starting from powders, have performed dose-response curves and have validated their actions as inhibitors of the hNTH1/YB-1 interface using alternative binding assays. Taken together, our results demonstrate that YB-1 directly interacts and stimulates a DNA repair and a DNA relaxing enzyme and targeting the YB-1/hNTH1 interface represents an interesting new strategy for the development of anti-cancer drugs