The hMre11/hRad50 Protein Complex and Nijmegen Breakage Syndrome: Linkage of Double-Strand Break Repair to the Cellular DNA Damage Response

Abstract

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by increased cancer incidence, cell cycle checkpoint defects, and ionizing radiation sensitivity. We have isolated the gene encoding p95, a member of the hMre11/hRad50 double-strand break repair complex. The p95 gene mapped to 8q21.3, the region that contains the NBS locus, and p95 was absent from NBS cells established from NBS patients. p95 deficiency in these cells completely abrogates the formation of hMre11/hRad50 ionizing radiation-induced foci. Comparison of the p95 cDNA to the NBS1 cDNA indicated that the p95 gene and NBS1 are identical. The implication of hMre11/hRad50/p95 protein complex in NBS reveals a direct molecular link between DSB repair and cell cycle checkpoint functions.

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.…”

“…It is required for nucleotide-dependent DNA binding by the complex and ATP-dependent DNA unwinding, suggesting that Nbs1 regulates MR catalytic functions (Lee et al, 2003a). In NBS cells, which contain very low levels of the p70 form of Nbs1, Mre11 and Rad50 were shown to be distributed in the cytoplasm, suggesting that Nbs1 is required for nuclear localization of these proteins (Carney et al, 1998;Difilippantonio et al, 2005). Mapping of the domains within the Nbs1 protein showed that a 101 amino-acid domain in the Nbs1 C-terminus interacts with a 319 amino-acid domain in the N-terminus of Mre11 (DesaiMehta et al, 2001).…”

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.…”

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

“…Nibrin (NBN), a member of the trimeric complex formed by MRE11, RAD50, and NBN (MRN), is involved in several phases of the DNA double-strand break (DSB) damage response, including sensing, signaling, and repair of DNA lesions (1,2). After DNA damage, several proteins involved in the damage response (including MRN) accumulate in large subnuclear structures, called ionizing radiation-induced nuclear foci (IRIF) (3)(4)(5).…”

“…The majority of patients with NBS are homozygous for the 657del5 hypomorphic mutation in exon 6 of NBN (1,25). This mutation determines the synthesis of two fragments of NBN with molecular weights of 26 and 70 kDa.…”