Host: The Japan Radiation Research Society
Nijmegen breakage syndrome(NBS), characterized by high sensitivity to ionizing radiation (IR) and predisposition to lymphoid cancer, is phenotypically similar to Ataxia telangiectasia. It is well known that NBS1, the protein responsible for NBS, is cooperative with ATM, mutated in AT, for IR-induced DNA damage response such as double-strand break repair and cell cycle checkpoints. Recently, it was also reported that NBS shares common clinical signs with ATR-defective Seckel syndrome, such as microcephaly, and NBS cells is similarly defective in response to hydoxyurea treatment. Since ATR, a family gene of ATM kinase, functions in stalled replication fork after HU treatment or UV exposure, NBS1 might associate with ATR during stalling replication forks. Our result showed that UV-induced TopBP1 foci were abolished in NBS cells, suggesting that TopBP1 foci formation is regulated by NBS1. Co-immunoprecipitation assays showed that NBS1 interacts with TopBP1 in a manner that depends on UV-induced damage. These results indicated that TopBP1 functions downstream of NBS1 and mediates DNA damaging signal to ATR.
