¹Department of Environmental Sciences, Ibaraki University, Mito, Ibaraki 310-8512, Japan

²Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan

³Department of Oral and Maxillo Facial Radiology, Hiroshima University, Hiroshima 734-8553, Japan

⁴Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan

Correspondence to: K Komatsu, E-mail: komatsu@house.rbc.kyoto-u.ac.jp

DNA double-strand breaks represent the most potentially serious damage to a genome and hence, at least two pathways of DNA repair have evolved; namely, homologous recombination repair and non-homologous end joining. Defects in both rejoining processes result in genomic instability including chromosome rearrangements, LOH and gene mutations, which may lead to development of malignancies. Nijmegen breakage syndrome is a recessive genetic disorder, characterized by elevated sensitivity to ionizing radiation that induces double-strand breaks, and high frequency of malignancies. NBS1, the product of the gene underlying the disease, forms a multimeric complex with hMRE11/hRAD50 nuclease and recruits them to the vicinity of sites of DNA damage by direct binding to phosphorylated histone H2AX. The combination of the highly-conserved NBS1 forkhead associated domain and BRCA1 C-terminus domain has a crucial role for recognition of damaged sites. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates. This process collaborates with cell-cycle checkpoints at S and G2 phase to facilitate DNA repair. NBS1 is also associated with telomere maintenance and DNA replication. Based on recent knowledge regarding NBS1, we propose here a two-step binding mechanism for damage recognition by repair proteins, and describe the molecular links to factors for genome stability.

Oncogene (2002) 21, 8967-8980. doi:10.1038/sj.onc.1206136

Nijmegen breakage syndrome; NBS1; Mre11; histone H2AX; double-strand break; two-step binding model