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dc.contributor.authorDe Haro, Leyma
dc.date.accessioned2010-06-25T22:09:54Z
dc.date.available2010-06-25T22:09:54Z
dc.date.issued2010-06-25T22:09:54Z
dc.date.submittedMay 2009
dc.identifier.urihttp://hdl.handle.net/1928/10863
dc.description.abstractMetnase is a recently evolved human protein with methylase (SET) and nuclease domains that is widely expressed, especially in proliferating tissues. Metnase promotes plasmid and viral DNA integration, and through an interaction with topoisomerase IIα (TopoIIα) it promotes chromosome decatenation. Metnase interacts with DNA ligase IV, promotes non-homologous end-joining (NHEJ), and repression causes mild hypersensitivity to ionizing radiation. TopoIIα has a proposed role in relaxing positive supercoils in front of replication forks. NHEJ factors have been implicated in the replication stress response. Here we show that Metnase promotes cell proliferation, but does not affect replication fork elongation as measured by cell cycle analysis, BrdU incorporation and DNA fiber analysis. Even though there is no elongation effect, Metnase confers resistance to three replication stress agents, hydroxyurea, UV light, and the topoisomerase I inhibitor, camptothecin. Metnase expression also increases the rate at which H2AX phosphorylation (a marker of stalled or collapsed replication forks) is resolved. There was no difference in formation of gamma-H2AX foci after exposure to these agents. Metnase coimmunoprecipitates (co-IP) with proliferating cell nuclear antigen (PCNA) and RAD9. Finally, we show that Metnase promotes TopoIIα-mediated relaxation of positively supercoiled DNA, similar to the torsional strain preceding replication forks. These results establish Metnase as an important component of the human replication stress response.en_US
dc.description.sponsorshipNational Institutes of Healthen_US
dc.language.isoen_USen_US
dc.subjectMetnaseen_US
dc.subjectDNA replication stressen_US
dc.subjectDNA damageen_US
dc.subjectnon-homologous end joiningen_US
dc.subjecthydroxyureaen_US
dc.subjectreplication forken_US
dc.subject.lcshDNA replication--Regulation.
dc.subject.lcshDNA damage.
dc.subject.lcshCell proliferation--Molecular aspects.
dc.titleThe role of metnase in DNA replication fork stress response and DNA damageen_US
dc.typeDissertationen_US
dc.description.degreeBiomedical Sciencesen_US
dc.description.levelDoctoralen_US
dc.description.departmentUniversity of New Mexico. Biomedical Sciences Graduate Programen_US
dc.description.advisorHromas, Robert
dc.description.committee-memberOsley, Mary Ann
dc.description.committee-memberNickoloff, Jac
dc.description.committee-memberHudson, Laurie
dc.description.committee-memberChackerian, Bryce
dc.description.committee-memberWilliamson, Elizabeth


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