ENHANCED PHOSPHORYLATION OF P53 BY ATN IN RESPONSE TO DNA-DAMAGE

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