The Mre11/Rad50/Nbs1 complex and its role as a DNA double-strand break sensor for ATM

Double-strand breaks (DSBs) in chromosomal DNA elicit a rapid signaling response through the ATM protein kinase. Recent evidence suggests that the DNA repair complex containing Mre11, Rad50 and Nbs1 (MRN) is important for the activation of ATM by DSBs in cells. Our studies of the effects of MRN on ATM activity in vitro indicated that MRN stimulates ATM through multiple protein-protein contacts, and that this interaction increases the affinity of ATM for its substrates. Recently we isolated dimeric forms of ATM, which require MRN for activity but also require DNA, similar to the requirements for ATM activation and activity in vivo. Here we discuss the distinct characteristics of dimeric ATM, the role of MRN in recruiting ATM to DNA, the importance of DNA unwinding by MRN, and the role of autophosphorylation in ATM activation.