2. Academic Validation
  3. Cell stretching activates an ATM mechano-transduction pathway that remodels cytoskeleton and chromatin

Cell stretching activates an ATM mechano-transduction pathway that remodels cytoskeleton and chromatin

  • Cell Rep. 2023 Dec 11;42(12):113555. doi: 10.1016/j.celrep.2023.113555.
Giulia Bastianello 1,  Giancarlo Porcella 2,  Galina V Beznoussenko 2,  Gururaj Kidiyoor 2,  Flora Ascione 2,  Qingsen Li 2,  Angela Cattaneo 3,  Vittoria Matafora 2,  Andrea Disanza 2,  Micaela Quarto 2,  Alexander A Mironov 2,  Amanda Oldani 2,  Sara Barozzi 2,  Angela Bachi 2,  Vincenzo Costanzo 4,  Giorgio Scita 4,  Marco Foiani 5
Affiliations

Affiliations

  • 1 IFOM, the FIRC Institute of Molecular Oncology, 20139 Milan, Italy; Oncology and Haemato-Oncology Department, University of Milan, 20122 Milan, Italy. Electronic address: giulia.bastianello@ifom.eu.
  • 2 IFOM, the FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
  • 3 Cogentech SRL Benefit Corporation, 20139 Milan, Italy.
  • 4 IFOM, the FIRC Institute of Molecular Oncology, 20139 Milan, Italy; Oncology and Haemato-Oncology Department, University of Milan, 20122 Milan, Italy.
  • 5 IFOM, the FIRC Institute of Molecular Oncology, 20139 Milan, Italy; Oncology and Haemato-Oncology Department, University of Milan, 20122 Milan, Italy. Electronic address: marco.foiani@ifom.eu.
PMID: 38088930 DOI: 10.1016/j.celrep.2023.113555
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.

Keywords

ATM and ATR; CP: Cell biology; CP: Molecular biology; DNA damage response; ROS; ataxia telangiectasia; cell stretching; checkpoints; chromatin; cytoskeleton; interstitial migration; mechanical stress.

Figures
Products