Histone H3.3 and its proteolytically processed form drive a cellular senescence programme.
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.
1] 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.
Luis F
LF
Duarte
Cancer Research UK Cambridge Institute, University of Cambridge, The Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Andrew R J
AR
Young
1] Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA [2] Department of Pharmacology and Systems Therapeutics and Systems Biology Center New York (SBCNY), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.
Zichen
Z
Wang
1] Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA [2] Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.
Hsan-Au
HA
Wu
1] 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.
Taniya
T
Panda
1] Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA [2] Department of Pharmacology and Systems Therapeutics and Systems Biology Center New York (SBCNY), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.
Yan
Y
Kou
1] 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.
Avnish
A
Kapoor
1] 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.
Dan
D
Hasson
1] 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.
Nicholas R
NR
Mills
Department of Pharmacology and Systems Therapeutics and Systems Biology Center New York (SBCNY), Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.
Avi
A
Ma'ayan
Cancer Research UK Cambridge Institute, University of Cambridge, The Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Masashi
M
Narita
1] 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.
Emily
E
Bernstein
D056668:Cathepsin L / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism / Q000502:physiology; D050684:E2F Transcription Factors / Q000378:metabolism; D000066630:Ectopic Gene Expression / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D006657:Histones / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology; D009707:Nucleosomes / Q000378:metabolism / Q000502:physiology; D059748:Proteolysis; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology
D002843:Chromatin; D050684:E2F Transcription Factors; D006657:Histones; D009707:Nucleosomes; D012097:Repressor Proteins; C534281:CTSL protein, human; D056668:Cathepsin L