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

Martin Steger, Olga Murina, Daniela Hühn, Lorenza P Ferretti, Reto Walser, Kay Hänggi, Lorenzo Lafranchi, Christine Neugebauer, Shreya Paliwal, Pavel Janscak, Bertran Gerrits, Giannino Del Sal, Oliver Zerbe, Alessandro A Sartori

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)333-43
Number of pages11
JournalMolecular Cell
Volume50
Issue number3
DOIs
Publication statusPublished - 9 May 2013

Keywords

  • Cyclin-Dependent Kinase 2
  • DNA Breaks, Double-Stranded
  • DNA-Binding Proteins
  • Genomic Instability
  • Homologous Recombination
  • Peptidylprolyl Isomerase
  • Phosphorylation
  • Ubiquitination

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