1. Cell Biology
  2. Chromosomes and Gene Expression
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Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double-strand breaks

  1. Bryan A Leland
  2. Angela C Chen
  3. Amy Y Zhao
  4. Robert C Wharton
  5. Megan C King  Is a corresponding author
  1. Yale School of Medicine, United States
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Cite this article as: eLife 2018;7:e33402 doi: 10.7554/eLife.33402

Abstract

Poly(ADP ribose) polymerase inhibitors (PARPi) target cancer cells deficient in homology-directed repair of DNA double-strand breaks (DSBs). In preclinical models, PARPi resistance is tied to altered nucleolytic processing (resection) at the 5' ends of a DSB. For example, loss of 53BP1 or Rev7/MAD2L2/FANCV derepresses resection to drive PARPi resistance, although the mechanisms are poorly understood. Long-range resection can be catalyzed by two machineries: the exonuclease Exo1, or the combination of a RecQ helicase and Dna2. Here, we develop a single cell microscopy assay that allows the distinct phases and machineries of resection to be interrogated simultaneously in living S. pombe cells. Using this assay, we find that the 53BP1 orthologue and Rev7 specifically repress long-range resection through the RecQ helicase-dependent pathway, thereby preventing hyper-resection. These results suggest that 'rewiring' of BRCA1-deficient cells to employ an Exo1-independent hyper-resection pathway is a driver of PARPi resistance.

Article and author information

Author details

  1. Bryan A Leland

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Angela C Chen

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Amy Y Zhao

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Robert C Wharton

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Megan C King

    Department of Cell Biology, Yale School of Medicine, New Haven, United States
    For correspondence
    megan.king@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1688-2226

Funding

National Science Foundation (DGE-1122492)

  • Bryan A Leland

National Institutes of Health (DP2OD008429-01)

  • Megan C King

Searle Scholars Program (Scholar Award)

  • Megan C King

National Institutes of Health (T32-HD-007180-40)

  • Bryan A Leland

The Gruber Foundation (Gruber Science Fellowship)

  • Bryan A Leland

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Stephen C Kowalczykowski, University of California, Davis, United States

Publication history

  1. Received: November 8, 2017
  2. Accepted: April 11, 2018
  3. Accepted Manuscript published: April 26, 2018 (version 1)
  4. Version of Record published: May 10, 2018 (version 2)

Copyright

© 2018, Leland et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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