title: MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype.
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.
authors: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Hongshan
authors: H
authors: Chen
authors: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Penelope D
authors: PD
authors: Ruiz
authors: Department of Cell Biology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Wendy M
authors: WM
authors: McKimpson
authors: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Leonid
authors: L
authors: Novikov
authors: Department of Cell Biology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Richard N
authors: RN
authors: Kitsis
authors: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA. Electronic address: matthew.gamble@einstein.yu.edu.
authors: Matthew J
authors: MJ
authors: Gamble
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology*; D004249:DNA Damage; D059865:Endoplasmic Reticulum Stress; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009857:Oncogenes; D019899:Paracrine Communication; D010641:Phenotype
chemical_list: D006657:Histones; C120756:macroH2A histone; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins