MacroH2A1-induced SASP expression is required for OIS maintenance and is antagonized by ATM.

  • Major finding: MacroH2A1-induced SASP expression is required for OIS maintenance and is antagonized by ATM.

  • Mechanism: SASP activates an ER stress–ROS–ATM negative feedback loop to limit macroH2A1-driven transcription.

  • Impact: Regulation of macroH2A1 is critical for OIS-induced DDR and SASP autocrine/paracrine signaling.

Oncogene-induced senescence (OIS) is an important tumor-suppressive mechanism, characterized by proliferative arrest, morphologic changes, persistent DNA damage response (DDR), and activation of the senescence-associated secretory phenotype (SASP), a transcriptional program that promotes senescence via autocrine and paracrine signals. The transcriptional regulator histone variant macroH2A1 has been implicated as a tumor suppressor in various cellular functions, including senescence. To explore the role of macroH2A1 in SASP gene activation, Chen and colleagues assessed the genome-wide localization of macroH2A1 following mutant HRASV12 expression, and showed that macroH2A1 was recruited away from SASP genes in response to OIS. Although depletion of macroH2A1 did not inhibit HRASV12-induced senescence, it was associated with failed activation of the senescence-associated DDR, reduced SASP gene expression, and impaired senescence driven by exposure to SASP factor–containing conditioned media, suggesting that macroH2A1 is required to maintain senescence. Exogenous expression of macroH2A1.1, but not macroH2A1.2 or macroH2A1.1 mutants unable to interact with the transcriptional co-regulator PARP1, induced senescence, persistent DDR, and SASP gene expression. In line with this finding, chemical inhibition of PARP1 suppressed macroH2A1.1- or HRASV12-driven SASP gene expression. Stimulation of endoplasmic reticulum (ER) stress and subsequent accumulation of reactive oxygen species (ROS) were observed following HRASV12-driven OIS, macroH2A1.1-mediated senescence, and SASP-driven paracrine senescence, and were dependent on macroH2A1. Moreover, increasing levels of ER stress–induced ROS inhibited SASP gene expression, thereby limiting further ER stress, and OIS-induced relocalization of macroH2A1 and altered SASP gene expression were dependent on the DDR regulatory kinase ATM. Together, these data suggest a model in which macroH2A1 maintains autocrine/paracrine senescence signals by upregulating SASP gene expression, which activates an ROS-induced DDR/ATM–mediated negative feedback loop that limits persistent ER stress by removing macroH2A1 from SASP genes.

Chen H, Ruiz PD, McKimpson WM, Novikov L, Kitsis RN, Gamble MJ. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol Cell 2015 Aug 20 [Epub ahead of print].