Regulation of Cellular Senescence by Polycomb Chromatin Modifiers Through Distinct DNA Damage- And Histone Methylation-Dependent Pathways

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Differentiation / physiology
  • Cellular Senescence / physiology
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Damage*
  • DNA Replication
  • Down-Regulation
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • HEK293 Cells
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Methylation
  • Polycomb-Group Proteins / metabolism*
  • Up-Regulation

Substances

  • CDKN2A protein, human
  • Chromatin
  • Cyclin-Dependent Kinase Inhibitor p16
  • Histones
  • Polycomb-Group Proteins
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein