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Histone H3.3 and its proteolytically processed form drive a cellular senescence programme

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Listed:
  • Luis F. Duarte

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai)

  • Andrew R. J. Young

    (Cancer Research UK Cambridge Institute, University of Cambridge, The Li Ka Shing Centre)

  • Zichen Wang

    (Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Hsan-Au Wu

    (Icahn School of Medicine at Mount Sinai
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai)

  • Taniya Panda

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Yan Kou

    (Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Avnish Kapoor

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Present address: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA)

  • Dan Hasson

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Nicholas R. Mills

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Avi Ma’ayan

    (Icahn School of Medicine at Mount Sinai)

  • Masashi Narita

    (Cancer Research UK Cambridge Institute, University of Cambridge, The Li Ka Shing Centre)

  • Emily Bernstein

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

Abstract

The process of cellular senescence generates a repressive chromatin environment, however, the role of histone variants and histone proteolytic cleavage in senescence remains unclear. Here, using models of oncogene-induced and replicative senescence, we report novel histone H3 tail cleavage events mediated by the protease Cathepsin L. We find that cleaved forms of H3 are nucleosomal and the histone variant H3.3 is the preferred cleaved form of H3. Ectopic expression of H3.3 and its cleavage product (H3.3cs1), which lacks the first 21 amino acids of the H3 tail, is sufficient to induce senescence. Further, H3.3cs1 chromatin incorporation is mediated by the HUCA histone chaperone complex. Genome-wide transcriptional profiling revealed that H3.3cs1 facilitates transcriptional silencing of cell cycle regulators including RB/E2F target genes, likely via the permanent removal of H3K4me3. Collectively, our study identifies histone H3.3 and its proteolytically processed forms as key regulators of cellular senescence.

Suggested Citation

  • Luis F. Duarte & Andrew R. J. Young & Zichen Wang & Hsan-Au Wu & Taniya Panda & Yan Kou & Avnish Kapoor & Dan Hasson & Nicholas R. Mills & Avi Ma’ayan & Masashi Narita & Emily Bernstein, 2014. "Histone H3.3 and its proteolytically processed form drive a cellular senescence programme," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6210
    DOI: 10.1038/ncomms6210
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    Cited by:

    1. Janne Purhonen & Rishi Banerjee & Vilma Wanne & Nina Sipari & Matthias Mörgelin & Vineta Fellman & Jukka Kallijärvi, 2023. "Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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