Analysis of regulatory mechanisms of translesion DNA synthesis in human cells
| Project/Area Number |
17590059
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
MASUTANI Chikahide Osaka University, Graduate school of Frontier Biosciences, Associate Professor, 生命機能研究科, 助教授 (40241252)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | xeroderma pigmentosum / translesion DNA synthesis / DNA repair / DNA damage tolerance / ubiquitin / Rev1 / DNA polymerase eta / 色素性乾皮症バリアント / DNA複製 / タンパク質間相互作用 / ポリメラーゼ・スィッチング / クロマチン |
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| Research Abstract |
We have identified human DNA polymerase eta (pol eta) as the responsible gene product of xeroderma pigmentosum variant (XPV), an ultraviolet light sensitive genetic disease accompanied with cancer proneness. We have shown that pol eta catalyzes relatively accurate translesion DNA synthesis past cyclobutane pyrimidine dimers, the most frequent lesions induced by UV-irradiation to DNA. Pol eta, however, is never accurate DNA polymerase and actually induces mutations if it replicated undamaged DNA templates. These previous observations strongly indicate that cells must have regulatory mechanisms to control pol eta. To address them, protein-protein interactions between pol eta and related proteins are examined and identified Rev1 and Rad6/Rad18 complex as interacting proteins with pol eta. Rev1 re-localizes UV-induced lesions in cells as well as pol eta. Importantly, accumulation of Rev1 to damaged DNA locus is largely dependent on pol eta. Rev1 is known to interact with other translesion DNA polymerases in addition to pol eta. So, it is likely that Rev1 plays an important role in polymerase switches between translesion polymerases. Interaction of pol eta and Rad6/Rad18, and also Rev1, is enhanced on the chromatin DNA by inducing replication arrests by UV-irradiation or some drugs. Rad6/Rad18 is responsible for mono-ubiquitylation of PCNA, the sliding clamp for DNA replication polymerases. The modification is thought to be an key event for the polymerase switch between replicative and translesion polymerases. These results gave a great molecular evidences to understand regulatory mechanisms of translesion synthesis in human cells.
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Report
(3 results)
Research Products
(21 results)
