期刊
NUCLEIC ACIDS RESEARCH
卷 42, 期 21, 页码 13074-13081出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku978
关键词
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资金
- 973 project [2013CB911002]
- National Natural Science Foundation of China (NSFC) [31130017, 31461143012]
- Scientific Research Base Development Program of the Beijing Municipal Commission of Education
- Research Fund for the Doctoral Program of Higher Education of China [20101108110002]
- NSFC [31271446]
CLASPIN is an essential mediator in the DNA replication checkpoint, responsible for ATR (ataxia telangiectasia and Rad3-related protein)-dependent activation of CHK1 (checkpoint kinase 1). Here we found a dynamic signaling pathway that regulates CLASPIN turn over. Under unperturbed conditions, the E3 ubiquitin ligase HERC2 regulates the stability of the deubiquitinating enzyme USP20 by promoting ubiquitination-mediated proteasomal degradation. Under replication stress, ATR-mediated phosphorylation of USP20 results in the disassociation of HERC2 from USP20. USP20 in turn deubiquitinates K48-linked-polyubiquitinated CLASPIN, stabilizing CLASPIN and ultimately promoting CHK1 phosphorylation and CHK1-directed checkpoint activation. Inhibition of USP20 expression promotes chromosome instability and xenograft tumor growth. Taken together, our findings demonstrated a novel function of HERC2/USP20 in coordinating CHK1 activation by modulating CLASPIN stability, which ultimately promotes genome stability and suppresses tumor growth.
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