ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks

It is generally thought that the DNA- damage checkpoint kinases, ataxia- telangiectasia mutated ( ATM) and ATM- and Rad3-related ( ATR), work independently of one another. Here, we show that ATM and the nuclease activity of meiotic recombination 11 ( Mre11) are required for the processing of DNA double- strand breaks ( DSBs) to generate the replication protein A ( RPA)- coated ssDNA that is needed for ATR recruitment and the subsequent phosphorylation and activation of Chk1. Moreover, we show that efficient ATM- dependent ATR activation in response to DSBs is restricted to the S and G2 cell cycle phases and requires CDK kinase activity. Thus, in response to DSBs, ATR activation is regulated by ATM in a cell- cycle dependent manner.