Prolyl Isomerase PIN1 Regulates DNA Double-Strand Break Repair by Counteracting DNA End Resection

Mol Cell. 2013 May 9;50(3):333-43. doi: 10.1016/j.molcel.2013.03.023. Epub 2013 Apr 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism
  • DNA / genetics*
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Genomic Instability
  • HEK293 Cells
  • Homologous Recombination
  • Humans
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Peptidylprolyl Isomerase / genetics*
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphorylation
  • Ubiquitination

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Nuclear Proteins
  • DNA
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • RBBP8 protein, human
  • PIN1 protein, human
  • Peptidylprolyl Isomerase