Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability.

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/ hRADS0 nuclease and recruits them to the vicinity of sites of DNA damage by direct binding to phosphory!ated histone H2AX. The combination of the highlyconserved NBS1 forkhead associated domain and BRCA1 C-terminus domain has a crucial role for recognition of damaged sites. Thereafter, the NBS1complex 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. [ABSTRACT FROM AUTHOR]