Competition between NBS1 and ATMIN Controls ATM Signaling Pathway Choice

Ataxia telangiectasia mutated (ATM) protein kinase activation by DNA double-strand breaks (DSBs) requires the Mre11-Rad50-NBS1 (MRN) complex, whereas ATM interactor (ATMIN) protein is required for ATM signaling induced by changes in chromatin structure. We show here that NBS1 and ATMIN proteins compete for ATM binding and that this mechanism controls ATM function. DSB-induced ATM substrate phosphorylation was increased in atmin mutant cells. Conversely, NBS1 deficiency resulted in increased ATMIN-dependent ATM signaling. Thus, the absence of one cofactor increased flux through the alternative pathway. Notably, ATMIN deficiency rescued the cellular lethality of NBS1-deficient cells, and NBS1/ATMIN double deficiency resulted in complete abrogation of ATM signaling and profound radiosensitivity. Hence, ATMIN and NBS1 mediate all ATM signaling by DSBs, and increased ATMIN-dependent ATM signaling explains the different phenotypes of nbs1- and atm-mutant cells. Thus, the antagonism and redundancy of ATMIN and NBS1 constitute a crucial regulatory mechanism for ATM signaling and function. [Display omitted] ► ATMIN and NBS1 compete for ATM interaction ► Absence of ATMIN enhances DSB-induced ATM signaling ► NBS1/ATMIN double deficiency results in complete abrogation of ATM signaling Activation of the protein kinase ATM by DNA double-strand breaks requires the MRN complex (Mre11-Rad50-NBS1), whereas activation by changes in chromatin structure requires the ATM interactor protein ATMIN. Behrens and colleagues show that NBS1 and ATMIN compete for ATM binding and that this mechanism controls ATM function. Radiation-induced ATM signaling was abrogated in double mutants, increasing radiosensitivity, but other nbs1-null phenotypes were improved by ATMIN deficiency. Hence, ATMIN-dependent ATM signaling explains the different phenotypes of nbs1- and atm-mutant cells.