title: Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation.
abstract: We report crosstalk between three senescence-inducing conditions, DNA damage response (DDR) defects, oxidative stress (OS) and nuclear shape alterations. The recessive autosomal genetic disorder Ataxia telangiectasia (A-T) is associated with DDR defects, endogenous OS and premature ageing. Here, we find frequent nuclear shape alterations in A-T cells, as well as accumulation of the key nuclear architecture component lamin B1. Lamin B1 overexpression is sufficient to induce nuclear shape alterations and senescence in wild-type cells, and normalizing lamin B1 levels in A-T cells reciprocally reduces both nuclear shape alterations and senescence. We further show that OS increases lamin B1 levels through p38 Mitogen Activated Protein kinase activation. Lamin B1 accumulation and nuclear shape alterations also occur during stress-induced senescence and oncogene-induced senescence (OIS), two canonical senescence situations. These data reveal lamin B1 as a general molecular mediator that controls OS-induced senescence, independent of established Ataxia Telangiectasia Mutated (ATM) roles in OIS.
authors.affiliation: CNRS, UMR217, Fontenay aux Roses, France.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Barascu
authors.forename: Catherine
authors.initials: C
authors.lastname: Le Chalony
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pennarun
authors.forename: Diane
authors.initials: D
authors.lastname: Genet
authors.forename: Naima
authors.initials: N
authors.lastname: Imam
authors.forename: Bernard
authors.initials: B
authors.lastname: Lopez
authors.forename: Pascale
authors.initials: P
authors.lastname: Bertrand
mesh_terms: D000375:Aging; D002478:Cells, Cultured; D006801:Humans; D034921:Lamin Type B / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D034921:Lamin Type B; D048051:p38 Mitogen-Activated Protein Kinases