Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Mol Cell. 2013 May 9;50(3):333-43. doi: 10.1016/j.molcel.2013.03.023. Epub 2013 Apr 25.
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 proteasomal degradation. Collectively, these data uncover PIN1-mediated isomerization as a regulatory mechanism coordinating DSB repair.
磷酸化依赖的信号通路对 DNA 双链断裂（DSB）修复的调控对于维持基因组稳定性至关重要；然而，人们对磷酸化如何控制 DSB 修复的分子机制知之甚少。在这里，我们发现 PIN1，一种磷酸化特异性脯氨酰异构酶，与关键的 DSB 修复因子相互作用，并影响同源重组（HR）和非同源末端连接（NHEJ）对 DSB 修复的相对贡献。我们发现 PIN1 缺陷细胞由于 DNA 末端切除增加而显示出减少的 NHEJ，而 PIN1 过表达细胞中的切除和 HR 受损。此外，我们鉴定出 CtIP 是 PIN1 的底物，并表明在表达对 PIN1 识别有抗性的 CtIP 突变体的细胞中，DSB 变得过度切除。在机制上，我们提供了证据表明，PIN1 通过促进 CtIP 的泛素化和随后的蛋白酶体降解来影响 CtIP 的稳定性。总之，这些数据揭示了 PIN1 介导的异构化作为协调 DSB 修复的调节机制。
