Disease relevance of NBN

• Nijmegen breakage syndrome (NBS) is a chromosomal fragility disorder that shares clinical and cellular features with ataxia telangiectasia [1].
• While NBS shares overlapping characteristics with ataxia telangiectasia, it also has features overlapping with ATR-Seckel (ATR: ataxia-telangiectasia and Rad3-related protein) syndrome, a subclass of Seckel syndrome mutated in ATR [2].
• To systematically explore the mechanism involved in the assembly of APBs, we examine the role of Nijmegen breakage syndrome 1 (NBS1) and TRF1 in this process, respectively [3].
• Nijmegen breakage syndrome, a chromosomal instability disorder, is characterized in part by cellular hypersensitivity to ionizing radiation [4].
• Defects in recombination or in repair mechanisms at the level of DNA breakage can lead to chromosomal aberrations, genetic instability, as well as cancer predisposition syndromes (i.e., NBS, ataxia-telangiectasia, Bloom syndrome) [5].
• These results indicate that NBS1 overexpression induces EMT through the upregulation of Snail expression, and co-expression of NBS1/Snail predicts metastasis in HNSCCs [6].
• We provide evidence of medulloblastomas characterized by NBS1 mutations typically associated with mutational inactivation of the TP53 gene [7].

Psychiatry related information on NBN

• The rare autosomal recessive Nijmegen breakage syndrome is characterised by severe immunodeficiency, microcephaly associated with mental retardation, and typical chromosomal rearrangements in peripheral T lymphocytes [8].
• STUDY DESIGN: The Centers for Disease Control and Prevention linked three data sources in Georgia: (1) Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP), (2) Special Education Database of Metropolitan Atlanta (SEDMA), and (3) State of Georgia Newborn Blood-Spot Screening Program (NBSP) [9].

High impact information on NBN

• Clinically, Seckel syndrome shares features in common with disorders involving impaired DNA-damage responses, such as Nijmegen breakage syndrome (OMIM 251260) and LIG4 syndrome (OMIM 606593) [10].
• In contrast, concomitant interference with Nbs1-Mre11 and the Chk2-Cdc25A-Cdk2 pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete RDS analogous to that caused by defective ATM [11].
• Here we show that experimental blockade of either the Nbs1-Mre11 function or the Chk2-triggered events leads to a partial RDS phenotype in human cells [11].
• We propose that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype [12].
• Nijmegen breakage syndrome (NBS) is a rare chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity and radioresistant DNA synthesis-S phase checkpoint deficiency, which results in the failure to suppress DNA replication origins following DNA damage [12].

Chemical compound and disease context of NBN

• Here we show that following treatment with the DNA-intercalating agent actinomycin D (ActD), normal quiescent T cells accumulate double-strand breaks and die, whereas T cells from ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) patients are resistant to this death pathway despite a comparable amount of DNA damage [13].
• We identified three serine residues (S19, S33, and S35) on Chk2 that became phosphorylated in vivo rapidly and exclusively in response to ionizing radiation (IR)-induced DNA double-strand breaks in an ATM- and Nbs1-dependent but ataxia telangiectasia- and Rad3-related-independent manner [14].
• Mutant Nbs1 enhances cisplatin-induced DNA damage and cytotoxicity in head and neck cancer [15].
• A double-blind crossover trial of oligofructose (Raftilose P95) 2 g three times daily against sucrose (1 g) three times daily was performed in patients suffering from irritable bowel syndrome [16].
• A 95 kDa membrane protein (P-95) has been previously noted to be overexpressed in a doxorubicin-resistant subline of the MCF-7 breast cancer line and in clinical samples obtained from patients with solid tumours refractory to doxorubicin [17].

Biological context of NBN

• There are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS) [18].
• Our data provide a biochemical explanation for the similarity in phenotype between A-T and NBS [18].
• ATM-dependent phosphorylation of nibrin in response to radiation exposure [18].
• NBS1p70 is produced by internal translation initiation within the NBS1 mRNA using an open reading frame generated by the 657del5 frameshift [12].
• Hypomorphic mutations in the NBS1 or MRE11 genes in humans result in conditions characterized by DNA damage sensitivity, cell cycle checkpoint deficiency, and high cancer incidence [19].

Anatomical context of NBN

• Nibrin localizes to chromosomal sites of class switching, and B cells from NBS patients show an enhanced presence of microhomologies at the sites of switch recombination [20].
• Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and AT-like disorder fibroblasts, which lack an S checkpoint response when exposed to ionizing radiation, responded normally when exposed to UVC and inhibited replicon initiation [21].
• Using small interfering RNA transfection, we have knocked down NBS1 protein levels and analyzed relevant phenotypes in two closely related human lymphoblastoid cell lines with different p53 status, namely wild-type TK6 and mutated WTK1 [22].
• Telomere instability in a human tumor cell line expressing NBS1 with mutations at sites phosphorylated by ATM [23].
• Here we have shown that constitutive expression of NBS1 in Rat1a and HeLa cells induces/enhances their transformation [24].

Associations of NBN with chemical compounds

• We also show that ATM physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro [18].
• Following HU-induced replication arrest, NBS and ATR-Seckel cells show similarly impaired G2/M checkpoint arrest and an impaired ability to restart DNA synthesis at stalled replication forks [2].
• The NH(2) terminus of NBS1, specifically the BRCA1 COOH-terminal domain, is required for this activity [3].
• Our results showed that Mre11 went through cell cycle-dependent phosphorylation upon sodium arsenite treatment and this post-translational modification required NBS1 but not ATM [25].
• Herein, we demonstrate that the chemotherapeutic enediyne antibiotic neocarzinostatin induced Rad51, but not NBS1, nuclear focus formation in a cell- cycle-dependent manner [26].
• Inhibition of Nbs1 phosphorylation by S343A mutant enhanced the antileukemia effect of the combination of imatinib and genotoxic agent [27].

Physical interactions of NBN

• The MRN complex is also involved in telomere maintenance, as demonstrated by the shortened telomeres in NBS primary human fibroblasts and the association of NBS1 with the telomere-binding protein TRF2 [23].
• Also recent findings that a protein associated with the MRE11/RAD50 repair complex is mutated in Nijmegen breakage syndrome characterized by increased cancer incidence and ionizing radiation sensitivity strongly support this idea [28].
• Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention [29].
• These findings suggest that the Nbs1/Mre11/Rad50 complex is not involved in coding end processing of V(D)J recombination [30].
• ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1 [31].

Enzymatic interactions of NBN

• Nijmegen breakage syndrome (NBS) cells stably transfected with an empty vector or with S343A-NBS1 or S278A/S343A phospho-mutants were unable to hyperphosphorylate RPA in DNA-damage-associated foci following HU treatment [32].

Regulatory relationships of NBN

• Strikingly, NBS promotes telomere elongation in conjunction with TERT in NBS fibroblasts [33].
• c-Myc directly regulates the transcription of the NBS1 gene involved in DNA double-strand break repair [34].
• In contrast, NBS cells show normal ability to activate ATM kinase following irradiation in vitro and in vivo [35].
• Finally, our analysis evidences a critical role of Nbs1 in the etoposide-induced inhibition of DNA replication in early S phase [36].
• In this study, we examined whether suppressed NBS1 expression by small interference RNA (siRNA) could enhance radiation sensitivity in cancer cells with different TP53 status [37].
• We report that NBS1 is an acetylated protein and that the acetylation level is tightly regulated by the SIRT1 deacetylase [38].

Other interactions of NBN

• Our findings suggest that Nbs1 functions in both ATR- and ATM-dependent signalling [2].
• We show that Nbs1 also facilitates ATR-dependent phosphorylation [2].
• Both patients were wild-type for ATM and NBS1, but compound heterozygotes for MRE11 gene mutations [1422C-->A, T481K; 1714C-->T, R571X] [39].
• Chk2 activation dependence on Nbs1 after DNA damage [40].
• Nbs1 and p53 contribute to both checkpoint and apoptosis pathways [41].

Analytical, diagnostic and therapeutic context of NBN

• Due to the role of ATM and NBS in tumor suppression and the response to chemotherapy and radiotherapy, these findings may assist in the development of a more rational approach to cancer treatment, as well as a better understanding of tumorigenesis [42].
• To determine the role of the FHA and BRCT domains in nibrin function, we have performed site-directed mutagenesis of conserved residues in these motifs [43].
• Sequence analysis of an 800-kb genomic DNA region on chromosome 8q21 that contains the Nijmegen breakage syndrome gene, NBS1 [44].
• Despite the clear hypersensitivity towards DSB-inducing agents, the overall rates of DSB-rejoining in NBS cells as measured by pulsed field gel electrophoresis were found to be very similar to those of wild type cells [45].
• We believe it could be a useful tool for: (1) confirming the NBS diagnosis in the presence of clinical signs of the disease; (2) identifying NBS heterozygotes and performing prenatal diagnosis in families with affected members; and (3) screening selected populations in which the frequency of NBS might be higher because of a founder effect [46].

References