Abstract
DNA damage induced apoptosis is a critical cellular function for the maintenance of genome stability. The NBS1 protein is a key regulator of DNA damage repair that acts by forming a complex with Rad50/Mre11 and by activating ATM. We found that NBS1 regulates a novel p53 independent apoptotic pathway in response to DNA damage. Experiments using a series of cell lines expressing mutant NBS1 proteins revealed that NBS1 is able to regulate the activation of Bax and Caspase-3 without the FHA, Mre11-binding, or the ATM-interacting domains, whereas the phosphorylation sites of NBS1 were essential for Bax activation. Interestingly, NBS1 regulates a novel Bax activation pathway by disrupting the Ku70-Bax complex which is required for activation of the mitochondrial apoptotic pathway. This dissociation of the Ku70-Bax complex can be mediated by acetylation of Ku70, and NBS1 can function in this process through a protein-protein interaction with Ku70. Thus, NBS1 functions in the prevention of carcinogenesis, not only through the precise repair of damaged DNA by homologous recombination, but also by its role in the elimination of inappropriately repaired cells.
