ATM associates with NBS1 for a cell cycle checkpoint regulation,

Abstract

NBS1, mutated in Nijmegen breakage syndrome, is involved in checkpoints and DNA repair after exposure to radiation. NBS1 forms foci at sites of radiation-induced double strand breaks and interacts with BRCA1/SMCI, which is crucial for S-checkpoint through SMC1 phosphorylation by ATM. Therefore, NBS1 modulate the ATM-dependent checkpoint possibly by binding to ATM at the extreme C-terminus of NBS1. On the other hands, NBS1 regulates homologous recombination repair through MRE11 nuclease, since HR-regulating ability of NBS1 is completely abolished by deletion of the MRE11-binding domain. In contrast, HR frequencies are only slightly affected both by mutations in the serine residues, which are phosphorylated by ATM kinase, and by deletion of the extreme C-terminus. This was also confirmed by findings that ATM defects did not reduce the HR repair frequency of an induced DSB. These results demonstrate that NBS1 is the key regulator for ATM-dependent checkpoint and that the function of NBS1 in HR repair of an induced DSB is independent of ATM.