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

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 and Emily Bernstein ()
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Luis F. Duarte: 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
Hsan-Au Wu: Icahn School of Medicine at Mount Sinai
Taniya Panda: Icahn School of Medicine at Mount Sinai
Yan Kou: Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai
Avnish Kapoor: Icahn School of Medicine at Mount Sinai
Dan Hasson: Icahn School of Medicine at Mount Sinai
Nicholas R. Mills: 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

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6210

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