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p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

Author

Listed:
  • Alexandre Prieur

    (INSERM, Avenir Team 'Genome Plasticity and Aging',–Functional Genomics Institute)

  • Emilie Besnard

    (INSERM, Avenir Team 'Genome Plasticity and Aging',–Functional Genomics Institute)

  • Amélie Babled

    (INSERM, Avenir Team 'Genome Plasticity and Aging',–Functional Genomics Institute)

  • Jean-Marc Lemaitre

    (INSERM, Avenir Team 'Genome Plasticity and Aging',–Functional Genomics Institute
    Centre Régional de Lutte contre le Cancer Val d'Aurelle-Paul Lamarque–208, rue des Apothicaires, Parc Euromédecine)

Abstract

Senescence is triggered by various cellular stresses that result in genomic lesions and DNA damage response activation. However, the role of chromatin and DNA replication in senescence induction remains elusive. Here we show that downregulation of p300 histone acetyltransferase activity induces senescence by a mechanism that is independent of the activation of p53, p21CIP1 and p16INK4A. This inhibition leads to a global H3, H4 hypoacetylation, initiating senescence-associated heterochromatic foci formation during S phase, together with a global decrease in replication fork velocity, and alteration of DNA replication timing. This replicative stress occurs without DNA damage and checkpoint activation, but results in a robust G2/M cell cycle arrest, within only one cell cycle. These results provide new insights into the control of S-phase progression by p300, and identify an unexpected chromatin-dependent alternative mechanism for senescence induction, which could possibly be exploited to treat cancer by senescence induction without generating further DNA damage.

Suggested Citation

  • Alexandre Prieur & Emilie Besnard & Amélie Babled & Jean-Marc Lemaitre, 2011. "p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression," Nature Communications, Nature, vol. 2(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1473
    DOI: 10.1038/ncomms1473
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    Cited by:

    1. Mark A. Sanborn & Xinge Wang & Shang Gao & Yang Dai & Jalees Rehman, 2025. "Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy," Nature Communications, Nature, vol. 16(1), pages 1-19, December.

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