Cleavage and inactivation of ATM during apoptosis

The activation of the cysteine proteases with aspartate specificity, termed caspases, is of fundamental importance for the execution of programmed cel l death. These proteases are highly specific in their action and activate o r inhibit a variety of key protein molecules in the cell. Here,,ve study th e effect of apoptosis on the integrity of two proteins that have critical r oles in DNA damage signalling, cell cycle checkpoint controls, and genome m aintenance-the product of the gene defective in ataxia telangiectasia, ATM, and the related protein ATR We find that ATM but not ATR is specifically c leaved in cells induced to undergo apoptosis by a variety of stimuli. We es tablish that ATM cleavage in vivo is dependent on caspases, reveal that ATM is an efficient substrate for caspase 3 but not caspase 6 in vitro, and sh ow that the in vitro caspase 3 cleavage pattern mirrors that in cells under going apoptosis. Strikingly, apoptotic cleavage of ATM in vivo abrogates it s protein kinase activity against p53 but has no apparent effect on the DNA binding properties of ATM. These data suggest that the cleavage of ATM dur ing apoptosis generates a kinase-inactive protein that acts, through its DN A binding ability, in a trans-dominant-negative fashion to prevent DNA repa ir and DNA damage signalling.