Cell stretching activates an ATM mechano-transduction pathway that remodels cytoskeleton and chromatin
Giulia Bastianello, Giancarlo Porcella, Galina V. Beznoussenko, Gururaj Rao Kidiyoor, Flora Ascione, Qingsen Li, Angela Cattaneo, Vittoria Matafora, Andrea Disanza, Micaela Quarto, Alexander A. Mirоnоv, Amanda Oldani, Sara Barozzi, Angela Bachi, Vincenzo Costanzo, Giorgio Scita, Marco Foiani
Abstract
Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) DNA damage response (DDR) kinases contain elastic domains. ATM also responds to reactive oxygen species (ROS) and ATR to nuclear mechanical stress. Mre11 mediates ATM activation following DNA damage; ATM mutations cause ataxia telangiectasia (A-T). Here, using in vivo imaging, electron microscopy, proteomic, and mechano-biology approaches, we study how ATM responds to mechanical stress. We report that cytoskeleton and ROS, but not Mre11, mediate ATM activation following cell deformation. ATM deficiency causes hyper-stiffness, stress fiber accumulation, Yes-associated protein (YAP) nuclear enrichment, plasma and nuclear membrane alterations during interstitial migration, and H3 hyper-methylation. ATM locates to the actin cytoskeleton and, following cytoskeleton stress, promotes phosphorylation of key cytoskeleton and chromatin regulators. Our data contribute to explain some clinical features of patients with A-T and pinpoint the existence of an integrated mechano-response in which ATM and ATR have distinct roles unrelated to their canonical DDR functions.