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Persistent repair intermediates induce senescence

Author

Listed:
  • F. M. Feringa

    (Netherlands Cancer Institute)

  • J. A. Raaijmakers

    (Netherlands Cancer Institute)

  • M. A. Hadders

    (Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 CG)

  • C. Vaarting

    (Netherlands Cancer Institute)

  • L. Macurek

    (Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague 4)

  • L. Heitink

    (Netherlands Cancer Institute
    Walter and Eliza Hall Institute of Medical Research, Parkville)

  • L. Krenning

    (Netherlands Cancer Institute
    The Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht)

  • R. H. Medema

    (Netherlands Cancer Institute)

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.

Suggested Citation

  • F. M. Feringa & J. A. Raaijmakers & M. A. Hadders & C. Vaarting & L. Macurek & L. Heitink & L. Krenning & R. H. Medema, 2018. "Persistent repair intermediates induce senescence," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06308-9
    DOI: 10.1038/s41467-018-06308-9
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    Cited by:

    1. Daan M. K. Soest & Paulien E. Polderman & Wytze T. F. Toom & Janneke P. Keijer & Markus J. Roosmalen & Tim M. F. Leyten & Johannes Lehmann & Susan Zwakenberg & Sasha Henau & Ruben Boxtel & Boudewijn M, 2024. "Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Hongwei Yao & Joselynn Wallace & Abigail L. Peterson & Alejandro Scaffa & Salu Rizal & Katy Hegarty & Hajime Maeda & Jason L. Chang & Nathalie Oulhen & Jill A. Kreiling & Kelsey E. Huntington & Moniqu, 2023. "Timing and cell specificity of senescence drives postnatal lung development and injury," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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