Enhanced Phosphorylation of p53 by ATM in Response to DNA Damage

TLDR

ATM, a PI3K‑related kinase encoded by the ataxia telangiectasia gene, regulates cellular responses to DNA breaks and shares its domain with other protein kinases. ATM phosphorylates p53 on serine‑15 in vitro and in vivo, a wortmannin‑sensitive activity that is enhanced by radiomimetic drugs and lost with ATM mutations, indicating a key role in DNA‑damage signaling.

Abstract

The ATM protein, encoded by the gene responsible for the human genetic disorder ataxia telangiectasia (A-T), regulates several cellular responses to DNA breaks. ATM shares a phosphoinositide 3-kinase–related domain with several proteins, some of them protein kinases. A wortmannin-sensitive protein kinase activity was associated with endogenous or recombinant ATM and was abolished by structural ATM mutations. In vitro substrates included the translation repressor PHAS-I and the p53 protein. ATM phosphorylated p53 in vitro on a single residue, serine-15, which is phosphorylated in vivo in response to DNA damage. This activity was markedly enhanced within minutes after treatment of cells with a radiomimetic drug; the total amount of ATM remained unchanged. Various damage-induced responses may be activated by enhancement of the protein kinase activity of ATM.