NBS1 and MRE11 associate for responses to DNA double-strand breaks

.Nijmegen breakage syndrome (NBS) is a rare recessive genetic disorder, characterized by bird-like facial appearance, early growth retardation, congenital microcephaly, immunodeficiency and high frequency of malignancies. NBS belongs to the so-called chromosome instability syndromes; in fact, NBS cells display spontaneous chromosomal aberrations and are hypersensitive to DNA double-strand break-inducing agents, such as ionizing radiations. NBS1 forms a multimeric complex with MRE11/RAD50 nuclease at the C-terminus and retains or recruits them at the vicinity of sites of DNA damage by direct binding to histone H2AX, which is phosphorylated by phosphoinositide (PI)3-kinase family, in response to DNA damage. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair, which is clearly indicated in chicken DT40 cells. NBS cells also show to be defective in the activation of intra-S phase checkpoint. The present results demonstrate that NBS1 is a major regulator of HR repair by mediating the localization of MRE11 to sites of DNA damage.