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Cell Rep. 2018 Mar 27;22(13):3480-3492. doi: 10.1016/j.celrep.2018.03.002.

Regulation of Cellular Senescence by Polycomb Chromatin Modifiers through Distinct DNA Damage- and Histone Methylation-Dependent Pathways.

Author information

1
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
2
Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA.
3
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA; Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA.
4
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. Electronic address: john_sedivy@brown.edu.

Abstract

Polycomb group (PcG) factors maintain facultative heterochromatin and mediate many important developmental and differentiation processes. EZH2, a PcG histone H3 lysine-27 methyltransferase, is repressed in senescent cells. We show here that downregulation of EZH2 promotes senescence through two distinct mechanisms. First, depletion of EZH2 in proliferating cells rapidly initiates a DNA damage response prior to a reduction in the levels of H3K27me3 marks. Second, the eventual loss of H3K27me3 induces p16 (CDKN2A) gene expression independent of DNA damage and potently activates genes of the senescence-associated secretory phenotype (SASP). The progressive depletion of H3K27me3 marks can be viewed as a molecular "timer" to provide a window during which cells can repair DNA damage. EZH2 is regulated transcriptionally by WNT and MYC signaling and posttranslationally by DNA damage-triggered protein turnover. These mechanisms provide insights into the processes that generate senescent cells during aging.

KEYWORDS:

CDKN1A; CDKN2A; DNA damage response; Polycomb group; WNT pathway; cell cycle checkpoints; cellular senescence; chromatin; proinflammatory cytokines; senescence-associated secretory phenotype

PMID:
29590617
PMCID:
PMC5915310
DOI:
10.1016/j.celrep.2018.03.002
[Indexed for MEDLINE]
Free PMC Article

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