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

Nature communications | Nov 14, 2014

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.

Pubmed ID: 25394905 RIS Download

Mesh terms: Cathepsin L | Cell Aging | Cell Cycle | Chromatin | E2F Transcription Factors | Ectopic Gene Expression | Fibroblasts | Histones | Humans | Melanocytes | Nucleosomes | Proteolysis | Repressor Proteins

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Associated grants

  • Agency: NCI NIH HHS, Id: NCI/NIH R01CA154683
  • Agency: NIGMS NIH HHS, Id: R01GM098316
  • Agency: NIGMS NIH HHS, Id: P50 GM071558
  • Agency: NHLBI NIH HHS, Id: U54 HL127624
  • Agency: NCI NIH HHS, Id: R01 CA154683
  • Agency: NCI NIH HHS, Id: T32 CA078207
  • Agency: NIGMS NIH HHS, Id: R01 GM098316
  • Agency: NCI NIH HHS, Id: T32CA078207
  • Agency: NCI NIH HHS, Id: U54 CA189201
  • Agency: NIGMS NIH HHS, Id: P50GM071558

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