Inhibition of ATM kinase rescues planarian regeneration after lethal radiation

Abstract

As stem cells divide, they acquire mutations that can be passed on to daughter cells. To mitigate potentially deleterious outcomes, cells activate the DNA damage response (DDR) network, which governs several cellular outcomes following DNA damage, including repairing DNA or undergoing 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 to withstand lethal doses of radiation which would otherwise induce cell death. 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 in planarians, ATM promotes radiation‐induced apoptosis. This acute, ATM‐dependent apoptosis is a key determinant of long‐term animal survival. Our results suggest that inhibition of ATM in these organisms could, therefore, potentially favor cell survival after radiation without obvious effects on stem cell behavior. image The DNA damage response kinase ATM drives stem cell apoptosis in radiated planarians. Knockdown of atm prevents stem cell apoptosis after radiation and enables long‐term animal survival and regeneration through a reliance on homologous recombination. Planarian ATM enforces the G1/S checkpoint and drives radiation‐induced stem cell apoptosis independently of its canonical effector p53. Knockdown of atm results in atypical stem cell survival in planarians exposed to high doses of radiation. Stem cells in radiated atm knockdown animals rely on homologous recombination to resume cycling and fuel long‐term animal survival and regeneration.