2013 Fiscal Year Final Research Report
The role of BRCA1-HERC2 complex in DNA replication fork progression and stress response
| Project/Area Number |
23590348
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | St. Marianna University School of Medicine |
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Principal Investigator |
WU WENWEN 聖マリアンナ医科大学, 医学部, 助教 (10434408)
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| Project Period (FY) |
2011 – 2013
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| Keywords | HERC2 / BRCA1 / Claspin / 複製フォーク / ＡＴＲＩＰ / ＭＣＭ２ |
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| Research Abstract |
HERC2 is an E3 ubiquitin ligase that targets breast cancer suppressor BRCA1 for degradation. Here we show that HERC2 is a component of the DNA replication fork complex that plays a critical role in DNA elongation and origin firing. In the presence of BRCA1, HERC2 interacts with Claspin, a protein essential for G2/M checkpoint activation and replication fork stability. Claspin depletion slowed S-phase rogression and additional HERC2 depletion reduced the effect of Claspin depletion. HERC2 interacts with replication fork complex proteins. Depletion of HERC2 alleviated the slow replication fork progression in Claspin-deficient cells, suppressed enhanced origin firing. During replication stress response, the amount of HERC2 is increased in the ATRIP complex, to result in an increase of MCM2 phosphorylation by ATR. HERC2, Claspin, and BRCA1 possibly cooperate on activation of Chk1 and Plk1 to regulate DNA replication progression and origin firing by facilitating MCM2 phosphrylation.
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