Prolyl isomerase PIN1 regulates DNA double-strand break repair by counteracting DNA end resection.

Research paper by Martin M Steger, Olga O Murina, Daniela D Hühn, Lorenza P LP Ferretti, Reto R Walser, Kay K Hänggi, Lorenzo L Lafranchi, Christine C Neugebauer, Shreya S Paliwal, Pavel P Janscak, Bertran B Gerrits, Giannino G Del Sal, Oliver O Zerbe, Alessandro A AA Sartori

Indexed on: 30 Apr '13Published on: 30 Apr '13Published in: Molecular Cell


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.