[PDF][PDF] Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage-and histone methylation-dependent pathways

T Ito, YV Teo, SA Evans, N Neretti, JM Sedivy - Cell reports, 2018 - cell.com
T Ito, YV Teo, SA Evans, N Neretti, JM Sedivy
Cell reports, 2018cell.com
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 …
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.
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