MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype

Hongshan Chen, Penelope D. Ruiz, Wendy M. McKimpson, Leonid Novikov, Richard N. Kitsis, Matthew J. Gamble

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Oncogene-induced senescence (OIS) is a tumor-suppressive mechanism typified by stable proliferative arrest, a persistent DNA damage response, and the senescence-associated secretory phenotype (SASP), which helps to maintain the senescent state and triggers bystander senescence in a paracrine fashion. Here, we demonstrate that the tumor suppressive histone variant macroH2A1 is a critical component of the positive feedback loop that maintains SASP gene expression and triggers the induction of paracrine senescence. MacroH2A1 undergoes dramatic genome-wide relocalization during OIS, including its removal from SASP gene chromatin. The removal of macroH2A1 from SASP genes results from a negative feedback loop activated by SASP-mediated endoplasmic reticulum (ER) stress. ER stress leads to increased reactive oxygen species and persistent DNA damage response including activation of ATM, which mediates removal macroH2A1 from SASP genes. Together, our findings indicate that macroH2A1 is a critical control point for the regulation of SASP gene expression during senescence. The histone variant macroH2A1 regulates transcription to affect various processes including tumor suppression. Chen et al. demonstrate that macroH2A1 promotes the transcription of SASP genes during oncogene-induced senescence. Additionally, macroH2A1 is antagonized by an ER stress pathway that leads to the ATM-dependent removal of macroH2A1 from SASP gene chromatin.

Original languageEnglish (US)
Pages (from-to)719-731
Number of pages13
JournalMolecular Cell
Volume59
Issue number5
DOIs
StatePublished - Sep 3 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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