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The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress.


ABSTRACT: ATR and Chk1 are two key protein kinases in the replication checkpoint. Activation of ATR-Chk1 has been extensively investigated, but checkpoint termination and replication fork restart are less well understood. Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. The protein levels of Chk1 and Fbx6 showed an inverse correlation in both cultured cancer cells and in human breast tumor tissues. Further, we show that low levels of Fbx6 and consequent impairment of replication stress-induced Chk1 degradation are associated with cancer cell resistance to the chemotherapeutic agent, camptothecin. We propose that Fbx6-dependent Chk1 degradation contributes to S phase checkpoint termination and that a defect in this mechanism might increase tumor cell resistance to certain anticancer drugs.

SUBMITTER: Zhang YW 

PROVIDER: S-EPMC2736145 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress.

Zhang You-Wei YW   Brognard John J   Coughlin Chris C   You Zhongsheng Z   Dolled-Filhart Marisa M   Aslanian Aaron A   Manning Gerard G   Abraham Robert T RT   Hunter Tony T  

Molecular cell 20090801 4


ATR and Chk1 are two key protein kinases in the replication checkpoint. Activation of ATR-Chk1 has been extensively investigated, but checkpoint termination and replication fork restart are less well understood. Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. The pr  ...[more]

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