Kenshi Komatsu
Research Institute for Radiation Biology and Medicine, Hiroshima University. Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan
(Tel: 81-82-257-5809, FAX: 81-82-256-7 101, e-mail: komatsu@hiroshima u.ac.)
Nijmegen breakage syndrome (NBS) is an autosomal recessive disease characterized by radiation sensitivity, chromosomal instability and a high incidence of cancer, which is similar to ataxia telangiectasia (AT). By using a complementation-assisted positional cloning, we identified a gene responsible for NBS, designated as NBS1, and the gene encodes 764 amino acids. NBSI protein showed a weak homology in the N-terminal region with budding yeast Xrs2 protein, which could function in the processing of double strand break (DSB) ends. Similar to Xrs2, NBS 1 forms a complex with hMre 11/hRad50 and recruits them to sites of DSB to initiate the homologous recombination and possibly non-homologous end-joining. This is consistent our observation that chicken DT40 NBS-/- cells abrogate the homologous recombination. The foci of triple-protein complex are observed 30-60 min after irradiation. Since our results showed that foci of phosphorylated histone H2AX are formed within a few min after DNA damage, the putative initial sensor could transduce signals to NBS I for DNA repair. Subsequently, we showed direct evidence that NBS l recruits the hMre I I nuclease complex into cell nuclear and leads to the formation of foci by utilizing different functions from several domains. The amino acid sequence at 665-693 on the C terminus of NBS1, where a novel identical sequence with yeast Xrs2 protein was found, is essential for hMre11 binding. The hMre11-binding region is necessary for both nuclear localization of the complex, and for cellular radiation resistance. In addition to DNA repair, our results showed that NBS1 is involved in an early apoptotic response to ionizing radiation and leads to killing of severely damaged cells. This might be related to high frequencies of congenital malformation in NBS patients, such as clinodactyly and syndactyly.
References:
(1) S.Matsuura, C.Weemaes, D.Smeets, H.Takami, N.Kondo, S.Sakamoto, N.Yano, A.Nakamura, H.Tauchi, S.Endo, M.Oshimura, K.Komatsu: Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen breakage syndrome at chromosome 8q21-24. (1997, Am.J.Hum.Genet., 60:1487-1494)
(2) S.Matsuura, H.Tauchi, A.Nakamura, N.Kondo, S.Sakamoto, S.Endo, D.Smeets, B.Solder, B.H.Belohradsky, V.M.D.Kaloustian, M.Oshimura, M.Isomura,Y.Nakamura, K.Komatsu:Positional cloning of the gene for Nijmegen breakage syndrome. (1998, Nature Genetics, 19: 179-181)
(3) H.Tauchi, J.Kobayashi, K.Morishima, S.Matsuura, A.Nakamura, T.Shiraishi,E.Ito, D.Masnada, D.Delia, K.Komatsu: The FHA domain of NBS1 is essential for nuclear foci formation after irradiation, but not essential for hRAD50/hMRE11/NBS1 complex DNA Repair activity. (2001, J. Biol. Chem., 276: 12-15)
Kenshi Komatsu, Ph.D. 1978 Ph.D. Tohoku University
1978-1 987 Research Scientist, Tohoku University
1987-1994 Assistant Professor, Nagasaki University
1994- Professor, Hiroshima University