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.
Paull
Tanya T
TT
Department of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas, Austin, Texas 78712, USA. tpaull@iamb.utexas.edu
Lee
Ji-Hoon
JH
D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes