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


Type

Article

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Authors

Duarte, Luis F 
Young, Andrew RJ 
Wang, Zichen 
Wu, Hsan-Au 
Panda, Taniya 

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.

Description

Keywords

Cathepsin L, Cell Cycle, Cellular Senescence, Chromatin, E2F Transcription Factors, Ectopic Gene Expression, Fibroblasts, Histones, Humans, Melanocytes, Nucleosomes, Proteolysis, Repressor Proteins

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

5

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (C14303/A17197)