MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype
| Autor: | Leonid Novikov, Richard N. Kitsis, Matthew J. Gamble, Penelope D. Ruiz, Wendy M. McKimpson, Hongshan Chen |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Senescence
DNA damage Paracrine Communication Ataxia Telangiectasia Mutated Proteins Biology Models Biological Article Cell Line Histones 03 medical and health sciences Paracrine signalling 0302 clinical medicine Humans Molecular Biology Cellular Senescence 030304 developmental biology Feedback Physiological Regulation of gene expression 0303 health sciences fungi Oncogenes Cell Biology Endoplasmic Reticulum Stress Chromatin Cell biology Phenotype Gene Expression Regulation 030220 oncology & carcinogenesis Unfolded protein response Cell aging DNA Damage |
| Zdroj: | Molecular Cell. 59:719-731 |
| ISSN: | 1097-2765 |
| Popis: | 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 stress. Endoplasmic reticulum 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|