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

Luis F Duarte1, Andrew R J Young2, Zichen Wang3

  • 11] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA [2] Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA [3] Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.

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|November 15, 2014
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Histone H3.3 cleavage by Cathepsin L is a novel regulator of cellular senescence. This process, involving histone variant H3.3 cleavage product (H3.3cs1), silences cell cycle genes and promotes senescence.

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Area of Science:

  • Epigenetics and Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Cellular senescence involves a repressive chromatin environment, but the roles of histone variants and proteolytic cleavage are not fully understood.
  • Histone modifications and variants are crucial for regulating gene expression and cellular processes like senescence.

Purpose of the Study:

  • To investigate the role of histone variants and proteolytic cleavage in cellular senescence.
  • To identify specific histone modifications and proteases involved in senescence-associated chromatin changes.

Main Methods:

  • Utilized models of oncogene-induced and replicative senescence.
  • Employed biochemical assays to detect histone cleavage events mediated by Cathepsin L.
  • Performed ectopic expression studies of histone H3.3 and its cleavage product (H3.3cs1).
  • Investigated chromatin incorporation mechanisms using the HUCA histone chaperone complex.
  • Conducted genome-wide transcriptional profiling to assess gene expression changes.

Main Results:

  • Identified novel histone H3 tail cleavage events mediated by the protease Cathepsin L.
  • Demonstrated that histone variant H3.3 is the preferred cleaved form of H3, generating H3.3cs1.
  • Showed that ectopic expression of H3.3 and H3.3cs1 is sufficient to induce cellular senescence.
  • Revealed that H3.3cs1 incorporation into chromatin is facilitated by the HUCA histone chaperone complex.
  • Found that H3.3cs1 promotes transcriptional silencing of cell cycle regulators, including RB/E2F target genes, potentially through H3K4me3 removal.

Conclusions:

  • Histone H3.3 and its proteolytically processed forms are key regulators of cellular senescence.
  • Cathepsin L-mediated cleavage of H3.3 contributes to the establishment of a senescence-associated repressive chromatin state.
  • H3.3cs1 acts as a senescence-inducing factor by silencing critical cell cycle genes.