Nibrin, a Novel DNA Double-Strand Break Repair Protein, Is Mutated in Nijmegen Breakage Syndrome

Abstract

Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Cells from NBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from ataxia telangiectasia. We describe the positional cloning of a gene encoding a novel protein, nibrin. It contains two modules found in cell cycle checkpoint proteins, a forkhead-associated domain adjacent to a breast cancer carboxy-terminal domain. A truncating 5 bp deletion was identified in the majority of NBS patients, carrying a conserved marker haplotype. Five further truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks.

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

“…Most of these studies were performed using cells derived from patients with Nijmegen Breakage Syndrome (NBS) or Ataxia-TelangiectasiaLike-Disorder (ATLD), which are caused by hypomorphic alleles of the Nbs1 or Mre11 genes, respectively (Carney et al, 1998;Varon et al, 1998;Stewart et al, 1999). The MRN complex was first considered to be in the same pathway with ATM because both NBS and ATLD patients exhibit similar clinical and cellular phenotypes compared to A-T patients, including chromosomal instability, radiation sensitivity and defects in cell cycle checkpoints.…”

DNA double-strand break repair and development

“…Hypomorphic mutations in Mre11 have been discovered in individuals exhibiting milder characteristics of A-T, resulting in A-T-like disease (ATLD) also characterized by neurodegeneration (Stewart et al, 1999). Likewise, hypomorphic mutations in NBS1 have been identified as the culprit in NBS (Carney et al, 1998;Varon et al, 1998). In contrast to A-T, NBS is characterized by microcephaly and is not associated with neurodegeneration or ataxia.…”

The role of ATM in DNA damage responses and cancer

“…The gene product defective in NBS, p95 or nibrin, is a component of the large multiprotein complex containing hRad50 and hMre11, nuclear proteins implicated in the NHEJ recombinational DNA repair pathway (Varon et al, 1998;Carney et al, 1998;Dolganov et al, 1996;Featherstone and Jackson, 1998). In response to IR, hMre11 and hRad50 form nuclear foci in close proximity to DSBs and the formation of these foci is markedly reduced in both NBS and AT cells (Maser et al, 1997;Dolganov et al, 1996;Carney et al, 1998;Nelms et al, 1998).…”