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  3. Persistent repair intermediates induce senescence

Persistent repair intermediates induce senescence

  • Nat Commun. 2018 Sep 25;9(1):3923. doi: 10.1038/s41467-018-06308-9.
F M Feringa 1,  J A Raaijmakers 1,  M A Hadders 2,  C Vaarting 1,  L Macurek 3,  L Heitink 1 4,  L Krenning 1 5,  R H Medema 6
Affiliations

Affiliations

  • 1 Oncode Institute, Division of Cell Biology, Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.
  • 2 Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands.
  • 3 Laboratory of Cancer Cell Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague 4, Prague, Czech Republic.
  • 4 ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
  • 5 Hubrecht Institute, The Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584CT, Utrecht, The Netherlands.
  • 6 Oncode Institute, Division of Cell Biology, Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands. R.Medema@nki.nl.
PMID: 30254262 DOI: 10.1038/s41467-018-06308-9
Abstract

Double-stranded DNA breaks activate a DNA damage checkpoint in G2 phase to trigger a cell cycle arrest, which can be reversed to allow for recovery. However, damaged G2 cells can also permanently exit the cell cycle, going into senescence or Apoptosis, raising the question how an individual cell decides whether to recover or withdraw from the cell cycle. Here we find that the decision to withdraw from the cell cycle in G2 is critically dependent on the progression of DNA repair. We show that delayed processing of double strand breaks through HR-mediated repair results in high levels of resected DNA and enhanced ATR-dependent signalling, allowing p21 to rise to levels at which it drives cell cycle exit. These data imply that cells have the capacity to discriminate breaks that can be repaired from breaks that are difficult to repair at a time when repair is still ongoing.

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