期刊
MOLECULAR CELL
卷 50, 期 3, 页码 333-343出版社
CELL PRESS
DOI: 10.1016/j.molcel.2013.03.023
关键词
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资金
- Swiss National Science Foundation [31003A-129747/1, 31003A_135507]
- Promedica Stiftung
- Vontobel-Stiftung
- Forschungskredit of the University of Zurich [54410102]
- Swiss National Science Foundation (SNF) [31003A_129747, 31003A_135507] Funding Source: Swiss National Science Foundation (SNF)
The regulation of DNA double-strand break (DSB) repair by phosphorylation-dependent signaling pathways is crucial for the maintenance of genome stability; however, remarkably little is known about the molecular mechanisms by which phosphorylation controls DSB repair. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, interacts with key DSB repair factors and affects the relative contributions of homologous recombination (HR) and nonhomologous end-joining (NHEJ) to DSB repair. We find that PIN1-deficient cells display reduced NHEJ due to increased DNA end resection, whereas resection and HR are compromised in PIN1-overexpressing cells. Moreover, we identify CtIP as a substrate of PIN1 and show that DSBs become hyperresected in cells expressing a CtIP mutant refractory to PIN1 recognition. Mechanistically, we provide evidence that PIN1 impinges on CtIP stability by promoting its ubiquitylation and subsequent proteasonnal degradation. Collectively, these data uncover PIN1 -mediated isomerization as a regulatory mechanism coordinating DSB repair.
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