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

Martin Steger1, Olga Murina, Daniela Hühn

  • 1Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Molecular Cell
|April 30, 2013
PubMed

Insights

PIN1 regulates DNA double-strand break (DSB) repair by controlling the balance between homologous recombination (HR) and nonhomologous end-joining (NHEJ). This phosphorylation-specific prolyl isomerase impacts CtIP stability, affecting DNA repair pathway choice.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • DNA double-strand breaks (DSBs) are critical DNA lesions requiring precise repair for genome stability.
  • Phosphorylation-dependent signaling pathways regulate DSB repair, but underlying mechanisms remain largely unknown.
  • The role of specific enzymes like PIN1 in coordinating DSB repair pathway choice is an emerging area of research.

Purpose of the Study:

  • To investigate the function of PIN1, a phosphorylation-specific prolyl isomerase, in the regulation of DNA double-strand break (DSB) repair.
  • To elucidate how PIN1 influences the balance between homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways.
  • To identify molecular targets of PIN1 involved in DSB repair pathway regulation.

Main Methods:

  • Cellular assays to assess DNA repair pathway choice (HR vs. NHEJ) in cells with altered PIN1 expression.
  • Analysis of protein-protein interactions between PIN1 and key DSB repair factors.
  • Biochemical experiments to identify and characterize substrates of PIN1, including CtIP.
  • Ubiquitylation and proteasomal degradation assays to determine the mechanism of PIN1 action.

Main Results:

  • PIN1 interacts with key DSB repair factors and modulates the relative contributions of HR and NHEJ.
  • PIN1 deficiency leads to reduced NHEJ and increased DNA end resection.
  • PIN1 overexpression compromises DNA end resection and HR.
  • CtIP is identified as a substrate of PIN1, and its interaction with PIN1 is crucial for regulating DNA end resection.
  • PIN1 promotes CtIP ubiquitylation and proteasomal degradation, impacting DSB repair.

Conclusions:

  • PIN1-mediated isomerization is a novel regulatory mechanism coordinating DSB repair.
  • PIN1 plays a critical role in balancing HR and NHEJ pathways by targeting CtIP for degradation.
  • Understanding PIN1's role provides insights into maintaining genome stability and potential therapeutic strategies for DNA repair deficiencies.

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