ATM Activation by Oxidative Stress

TLDR

ATM kinase is activated by DNA double‑strand breaks through the MRN complex and orchestrates DNA damage signaling, while ATM‑deficient cells are hypersensitive to oxidative stress. We demonstrate that ATM is directly activated by oxidation into a disulfide‑cross‑linked dimer, a process blocked by cysteine mutation, revealing ATM as a reactive‑oxygen‑species sensor independent of DNA breaks.

Abstract

The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.