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The role of metnase in DNA replication fork stress response and DNA damage


Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/10863

The role of metnase in DNA replication fork stress response and DNA damage

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dc.contributor.author De Haro, Leyma
dc.date.accessioned 2010-06-25T22:09:54Z
dc.date.available 2010-06-25T22:09:54Z
dc.date.issued 2010-06-25T22:09:54Z
dc.date.submitted May 2009
dc.identifier.uri http://hdl.handle.net/1928/10863
dc.description.abstract Metnase 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.sponsorship National Institutes of Health en_US
dc.language.iso en_US en_US
dc.subject Metnase en_US
dc.subject DNA replication stress en_US
dc.subject DNA damage en_US
dc.subject non-homologous end joining en_US
dc.subject hydroxyurea en_US
dc.subject replication fork en_US
dc.subject.lcsh DNA replication--Regulation.
dc.subject.lcsh DNA damage.
dc.subject.lcsh Cell proliferation--Molecular aspects.
dc.title The role of metnase in DNA replication fork stress response and DNA damage en_US
dc.type Dissertation en_US
dc.description.degree Biomedical Sciences en_US
dc.description.level Doctoral en_US
dc.description.department University of New Mexico. Biomedical Sciences Graduate Program en_US
dc.description.advisor Hromas, Robert
dc.description.committee-member Osley, Mary Ann
dc.description.committee-member Nickoloff, Jac
dc.description.committee-member Hudson, Laurie
dc.description.committee-member Chackerian, Bryce
dc.description.committee-member Williamson, Elizabeth

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