@article{58c7ce63498b476b87f884850744e16f,
title = "Histone H3.3 and its proteolytically processed form drive a cellular senescence programme",
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.",
author = "Duarte, {Luis F.} and Young, {Andrew R.J.} and Zichen Wang and Wu, {Hsan Au} and Taniya Panda and Yan Kou and Avnish Kapoor and Dan Hasson and Mills, {Nicholas R.} and Avi Ma'ayan and Masashi Narita and Emily Bernstein",
note = "Funding Information: We thank Elizabeth Duncan for critical reading of this manuscript. We thank Kajan Ratnakumar, Zulekha Qadeer, Hayley Zullow, Thomas Strub and Alexandre Gaspar-Maia for technical assistance. David Allis, Scott Lowe, Daniel Peeper, Jesus Gil, Hiroshi Kimura and Sandra Hake kindly provided reagents for these studies. We thank CRUK CI microscope facility for technical support. We also thank Madelaine Haddican, Shelbi Jim On and Giselle Singer in the Department of Dermatology for assistance with benign nevi collection, and Dr Mark Lebwohl for his continued support. This work was supported by Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",
year = "2014",
month = nov,
day = "14",
doi = "10.1038/ncomms6210",
language = "English",
volume = "5",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}