Abstract
Nijmegen breakage syndrome(NBS), characterized by high sensitivity to ionizing radiation (IR) and predisposition to lymphoid cancer, is phenotypically similar to ataxia telangiectasia (AT). NBS1, the protein responsible of disease, is cooperative with ATM, mutated in AT, in response to IR-induced DNA double-strand breaks (DSBs) and has crucial roles in DNA repair and cell cycle checkpoints. Recently, it was reported that when NBS cells are treated with hydroxyurea (HU), they show the phenotype similar to cells from Seckel syndrome, which is mutated in ATR and shares common clinical signs to NBS, such as microcephaly and growth retardation. Although ATM and ATR, a family of PI3-kinase, are key regulators for the checkpoint mechanisms, ATR is indispensable at stalled replication fork when cells are treated with HU or exposed to Ultraviolet (UV). To investigate the role of NBS1 for maintenance of replication fork, the cellular localization of NBS1 and the related proteins after exposure to UV-C were analyzed by immunostaining. NBS1 formed discrete foci after UV exposure and they co-localized with g-H2AX foci, which are formed at stalled replication forks. Interestingly, NBS1 mutant lacking FHA domain formed UV-induced foci. This is quite different from IR-induced foci, since FHA domain is essential for foci formation after IR irradiation, suggesting distinctive recruitment mechanism of NBS1 to replication fork. We will discuss more involvement of NBS1 in ATR-signaling at our poster session.
