Inhibition of the ATM kinase rescues planarian regeneration after lethal radiation

Abstract

AbstractAs stem cells divide, they acquire mutations that can be passed on to daughter cells. To limit the possibility of propagating mutations, cells activate the DNA damage response (DDR) network, which dictates whether cells repair DNA or undergo apoptosis. At the helm of the DDR are three PI3-like kinases including Ataxia Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells, which normally undergo apoptosis after radiation exposure, to survive lethal doses of radiation. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination-mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long-term and regenerate new tissues. These effects occur independently of ATM’s canonical downstream effector p53. Together, our results demonstrate that ATM’s primary function is to drive apoptosis, and suggest that inhibition of ATM could therefore potentially favor cell survival after radiation without adverse effects.