Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation

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 alterationsin A-T cells, as well as accumulation of the key nuclear architecture component laminB1. LaminB1 overexpression is sufficient to induce nuclear shape alterationsand senescencein wild-type cells, and normalizing laminB1 levels in A-T cells reciprocally reduces both nuclear shape alterationsand senescence. We further show that OS increases laminB1 levels through p38 Mitogen Activated Protein kinaseactivation. LaminB1 accumulation and nuclear shape alterationsalso occur during stress-induced senescenceand oncogene-induced senescence(OIS), two canonical senescencesituations. These data reveal laminB1 as a general molecular mediator that controls OS-induced senescence, independent of established Ataxia TelangiectasiaMutated (ATM) roles in OIS.