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REV7 counteracts DNA double-strand break resection and affects PARP inhibition

Guotai Xu1, J Ross Chapman2, Inger Brandsma3

  • 1Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.

Nature
|March 25, 2015
PubMed

Insights

Loss of REV7 restores homologous recombination (HR) DNA repair in BRCA1-deficient cells, leading to PARP inhibitor resistance. This REV7 function is downstream of 53BP1 and impacts DNA repair pathway choices.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Homologous recombination (HR) is crucial for error-free DNA double-strand break (DSB) repair.
  • BRCA1 deficiency leads to synthetic lethality with PARP inhibitors in certain cancers.
  • Drug resistance can arise from HR restoration, but mechanisms of BRCA1-independent HR restoration are unclear.

Purpose of the Study:

  • To investigate the mechanisms of BRCA1-independent HR restoration.
  • To identify novel factors involved in DNA repair pathway choice in BRCA1-deficient cells.
  • To understand the role of REV7 in DNA repair and PARP inhibitor resistance.

Main Methods:

  • Utilized mouse and human cell lines.
  • Investigated DNA repair pathways including HR and non-homologous end-joining (NHEJ).
  • Analyzed protein recruitment to DSBs using chromatin pathways.
  • Examined the effect of ATM kinase inhibition.

Main Results:

  • Loss of REV7 (MAD2L2) re-establishes CTIP-dependent end resection in BRCA1-deficient cells.
  • REV7 loss restores HR, conferring PARP inhibitor resistance.
  • REV7 recruitment to DSBs depends on the H2AX-MDC1-RNF8-RNF168-53BP1 pathway.
  • REV7 blocks DSB resection to promote NHEJ during immunoglobulin class switch recombination.
  • ATM kinase inhibition reverses REV7-mediated resistance.

Conclusions:

  • REV7 plays a critical role in blocking HR and promoting NHEJ in BRCA1-deficient cells.
  • REV7 acts downstream of 53BP1 in coordinating DSB repair pathway selection.
  • Targeting REV7 may offer strategies to overcome PARP inhibitor resistance.

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