A role for ATR in the DNA damage-induced phosphorylation of p53

Phosphorylation at Ser-15 may be a critical event in the up-regulation and functional activation of p53 during cellular stress. In this report we prov ide evidence that the ATM-Rad3-related protein ATR regulates phosphorylatio n of Ser-15 in DNA-damaged cells. Overexpression of catalytically inactive ATR (ATR(ki)) in human fibroblasts inhibited Ser-15 phosphorylation in resp onse to gamma-irradiation and UV light. In gamma-irradiated cells, ATR(ki) expression selectively interfered with late-phase Ser-15 phosphorylation, w hereas ATR(ki) blocked UV-induced Ser-15 phosphorylation in a time-independ ent manner. ATR phosphorylated p53 at Ser-15 and Ser-37 in vitro, suggestin g that p53 is a target for phosphorylation by ATR in DNA-damaged cells.