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

Abstract

Summary: 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. : Ito et al. show that downregulation of EZH2 rapidly elicits DNA damage and triggers the onset of senescence without loss of H3K27me3 marks. With slower kinetics, the depletion of H2K27me3 results in the upregulation of p16 and proinflammatory factors. WNT-MYC and ATM signaling are identified as upstream regulators of EZH2. Keywords: cellular senescence, chromatin, Polycomb group, senescence-associated secretory phenotype, proinflammatory cytokines, WNT pathway, DNA damage response, cell cycle checkpoints, CDKN1A, CDKN2A