Abstract 1267: The senescence-associated secretory phenotype requires the histone variant macroH2A1 and is antagonized by ATM in a novel ER stress response

Abstract

Abstract Oncogene induced senescence (OIS) is an important tumor suppressive mechanism typified by permanent proliferative arrest, a persistent DNA damage response and the senescent-associated secretory phenotype (SASP). MacroH2A1, a histone variant that plays tumor suppressive roles in a several cancer types is upregulated during OIS. Our ChIP-seq data demonstrate that SASP genes are found in macroH2A1-containing chromatin. Additionally, we found that macroH2A1 is a critical positive regulator of both the transcriptional upregulation of SASP genes and the persistent ATM activation seen during senescence. SASP factors participate in a positive feedback loop to maintain senescence through autocrine signaling and can also induce paracrine senescence in bystander cells. Strikingly, we find that cells depleted of macroH2A1 are immune to paracrine senescence triggered by SASP factors, indicating that macroH2A1 is a critical regulator of SASP positive feedback. Additionally, ectopic expression of macroH2A1.1, the macroH2A1 splice variant that is typically lost in cancer cells, is sufficient to trigger senescence in normal cells complete with a robust SASP response and persistent activation of ATM. Due to the increased expression of secreted factors, endoplasmic reticulum (ER) stress is a feature of OIS. ER stress has been shown to lead to the generation of reactive oxygen species which can cause DNA damage and ATM activation. We determined that ER stress, as assayed by the activation of the unfolded protein response, is reduced during OIS in cells depleted of macroH2A1. Furthermore, activated ATM participates in a novel negative feedback loop reducing SASP expression in response to ER stress by triggering the removal of macroH2A1 from SASP genes. Overall, our results demonstrate that SASP gene expression is regulated by the combined actions of a positive feedback loop that requires macroH2A1 and a negative feedback loop where ER stress leads to ATM activation critical for the removal of macroH2A1 from SASP genes and consequently their repression. Citation Format: Hongshan Chen, Penelope D. Ruiz, Wendy McKimpson, Leonid Novikov, Richard N. Kitsis, Matthew J. Gamble. The senescence-associated secretory phenotype requires the histone variant macroH2A1 and is antagonized by ATM in a novel ER stress response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1267. doi:10.1158/1538-7445.AM2015-1267