Cancersusceptibility disease Nijmegen Breakage Syndrome and the function of underlying gene.

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Nijmegen breakage syndrome (NBS) is a human hereditary disease, characterized by high sensitivity to radiation, chromosomal instability and predisposition to cancer, and the underlying gene, NBS1, reveals to code a repair protein, which lacks both nuclease activity and DNA-binding region. We presented here that NBS1 binds Mre11/Ras50 complex, a crucial nuclease for homologous recombination, at the C-terminus. Moreover, based on the evidence that histon H2AX is phosphorylated immediately after irradiation, we showed NBS1 binds to the phosphorylated histon through FHA/BRCT domains at the N-terminus. This binding was confirmed by both IP-western and in vitro binding assay. As a result, we proposed a damage response model, in which NBS1 recognizes damaged sites and initiates homologous recombination by recruitment of Mre11/Rad50 nuclease. In fact, analysis of homologous recombination using SCneo reporter gene showed significantly decreased homologous recombination in patient cells and mouse NBS cells. Furthermore, cohesin SMC1 binding to NBS1 and consequently SMC1 phosphorylation, a dispensable modification for S-checkpoint, were repressed in the clone lacking the C-terminus and N-terminus of NBS1. Similarly, NBS1 revealed to form the multi-protein complex including BRCA1 and WRN, mutated in Werner Syndrome, after irradiation. Since the disruption of complex formation results in chromosomal instability, it must be involved in maintenance of repair fidelity and cross-talk with checkpoint.