期刊
JOURNAL OF CELL BIOLOGY
卷 220, 期 8, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202008101
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资金
- National Institutes of Health [F31CA250366, F31CA236372, R00CA194309, R37CA240625]
- W. W. Smith Charitable Trust
- Penn State Cancer Institute postdoctoral fellowship
- National Cancer Institute Cancer Center [P30 CA060553]
- NIH Office of the Director instrumentation award [S10OD025194]
- National Resource for Translational and Developmental Proteomics by National Institutes of Health [P41 GM108569]
Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. The expression of DOT1L has been identified as an epigenetic regulator of the SASP, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
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