NBN (Nijmegen breakage syndrome 1)

2002-10-01   Nancy Uhrhammer , Jacques-Olivier Bay , Richard A Gatti 

Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France

Identity

HGNC
LOCATION
8q21.3
LOCUSID
ALIAS
AT-V1,AT-V2,ATV,NBS,NBS1,P95

DNA/RNA

Description

spans over 51 kb; 16 exons

Transcription

4.4 and 2.6 kb (alternative polyadenylation); open reading frame of 2265 nucleotides

Proteins

Description

the 754 amino acid protein is called nibrin; predicted MW 85 kDa, 95 kDa by SDS-PAGE; contains in N-term a forkhead associated domain (amino acids 24-100) and a breast cancer domain (BRCT; amino acids 105-190), both domains being found in the various DNA damage responsive cell cycle checkpoint proteins; 4 possible nuclear localization domains in the C-term half. Identified as the p95 subunit of the Rad50/Mre11/p95 double-strand DNA break repair complex. Nibrin is an essential component of this complex, and is responsible for its nuclear localization.

Expression

wide; shorter transcript expressed at higher level in the testis (plays a role in DNA damage repair, though not in meiotic recombination, as ATM does)

Function

member of the MRE/RAD50/nibrin double-strand break repair complex of 1600 kDa; necessary for localization of Rad50/Mre11 at DSB sites, and for the nucleolytic activities of this complex. Mice homozygous for null alleles of Nbs1 are inviable, while those with mutations corresponding to the common human mutation recapitulate the NBS phenotype. A 70 kDa protein containing the C-terminal portion of NBS1 produced from an alternative initiation site is associates with Rad50 and Mre11 and is apparently partially functional.

Homology

no known homology

Mutations

Germinal

missense mutations in the BRCT domain or truncating mutations downstream the BRCT are found in Nijmegen breakage syndrome (see below); most mutations are a 5 base deletion at codon 218, called 657del5, and are due to a founder effect

Somatic

Missense mutations in NBS1 have been associated with childhood acute lymphoblastic leukemia.

Implicated in

Entity name
Nijmegen breakage syndrome
Disease
Nijmegen breakage syndrome is a chromosome instability syndrome/cancer prone disease at risk of non Hodgkin lymphomas
Cytogenetics
chromosome rearrangements involving immunoglobulin superfamilly genes, in particular inv(7)(p13q35)

Bibliography

Pubmed IDLast YearTitleAuthors
114386752001Chk2 activation dependence on Nbs1 after DNA damage.Buscemi G et al
95901811998The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response.Carney JP et al
103918821999The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation upon DNA damage.Dong Z et al
92713791997Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation.Jongmans W et al
93156681997hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks.Maser RS et al
112795242001An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele.Maser RS et al
96207771998Positional cloning of the gene for Nijmegen breakage syndrome.Matsuura S et al
113258202001Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL).Varon R et al
95901801998Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.Varon R et al
119671512002A murine model of Nijmegen breakage syndrome.Williams BR et al
104269991999Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.Zhong Q et al
117560002001Decreased immunoglobulin class switching in Nijmegen Breakage syndrome due to the DNA repair defect.van Engelen BG et al

Other Information

Locus ID:

NCBI: 4683
MIM: 602667
HGNC: 7652
Ensembl: ENSG00000104320

Variants:

dbSNP: 4683
ClinVar: 4683
TCGA: ENSG00000104320
COSMIC: NBN

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000104320ENST00000265433O60934
ENSG00000104320ENST00000396252E2QRP0
ENSG00000104320ENST00000409330A0A0C4DG07
ENSG00000104320ENST00000517337E5RGN7
ENSG00000104320ENST00000517772E5RGR7
ENSG00000104320ENST00000519426E5RGU1
ENSG00000104320ENST00000523444E2QRP0
ENSG00000104320ENST00000613033A0A087X1V5

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Homologous recombinationKEGGko03440
Homologous recombinationKEGGhsa03440
MRN complexKEGGhsa_M00291
BRCA1-associated genome surveillance complex (BASC)KEGGhsa_M00295
MRN complexKEGGM00291
BRCA1-associated genome surveillance complex (BASC)KEGGM00295
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
G2/M DNA damage checkpointREACTOMER-HSA-69473
MeiosisREACTOMER-HSA-1500620
Meiotic recombinationREACTOMER-HSA-912446
DNA RepairREACTOMER-HSA-73894
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
DNA Damage/Telomere Stress Induced SenescenceREACTOMER-HSA-2559586
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
DNA Double Strand Break ResponseREACTOMER-HSA-5693606
Sensing of DNA Double Strand BreaksREACTOMER-HSA-5693548
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
Processing of DNA double-strand break endsREACTOMER-HSA-5693607
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
Resolution of D-Loop StructuresREACTOMER-HSA-5693537
Resolution of D-loop Structures through Holliday Junction IntermediatesREACTOMER-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)REACTOMER-HSA-5693554
HDR through Single Strand Annealing (SSA)REACTOMER-HSA-5685938
HDR through MMEJ (alt-NHEJ)REACTOMER-HSA-5685939
Nonhomologous End-Joining (NHEJ)REACTOMER-HSA-5693571
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
195974882009Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.634
157908082005ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.514
157589532005Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.456
213251342011BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair.301
150644162004Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex.257
121246282002Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex.246
174861122007Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair.198
180250842008PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites.192
198047552009Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate DNA double-strand break processing and repair.161
152018652004Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention.148

Citation

Nancy Uhrhammer ; Jacques-Olivier Bay ; Richard A Gatti

NBN (Nijmegen breakage syndrome 1)

Atlas Genet Cytogenet Oncol Haematol. 2002-10-01

Online version: http://atlasgeneticsoncology.org/gene/160/nbn

Historical Card

1999-10-01 NBN (Nijmegen breakage syndrome 1) by  Nancy Uhrhammer,Jacques-Olivier Bay,Richard A Gatti 

Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France

1998-11-01 NBN (Nijmegen breakage syndrome 1) by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France