ID:NBN_HUMAN DESCRIPTION: RecName: Full=Nibrin; AltName: Full=Cell cycle regulatory protein p95; AltName: Full=Nijmegen breakage syndrome protein 1; FUNCTION: Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11A. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. SUBUNIT: Component of the MRN complex composed of two heterodimers RAD50/MRE11A associated with a single NBN. Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50 and MRE11A (By similarity). Interacts with histone H2AFX this requires phosphorylation of H2AFX on 'Ser-139'. Interacts with HJURP, INTS3, KPNA2 and TERF2. Interacts with RBBP8; the interaction links the role of the MRN complex in DNA double-strand break sensing to resection. INTERACTION: P16104:H2AFX; NbExp=9; IntAct=EBI-494844, EBI-494830; Q14676:MDC1; NbExp=8; IntAct=EBI-494844, EBI-495644; P49959:MRE11A; NbExp=2; IntAct=EBI-494844, EBI-396513; Q96EB6:SIRT1; NbExp=5; IntAct=EBI-494844, EBI-1802965; SUBCELLULAR LOCATION: Nucleus (By similarity). Chromosome, telomere (By similarity). Note=Localizes to discrete nuclear foci after treatment with genotoxic agents (By similarity). TISSUE SPECIFICITY: Ubiquitous. Expressed at high levels in testis. DOMAIN: The FHA and BRCT domains are likely to have a crucial role for both binding to histone H2AFX and for relocalization of MRE11/RAD50 complex to the vicinity of DNA damage. DOMAIN: The C-terminal domain contains a MRE11-binding site, and this interaction is required for the nuclear localization of the MRN complex. DOMAIN: The EEXXXDDL motif at the C-terminus is required for the interaction with ATM and its recruitment to sites of DNA damage and promote the phosphorylation of ATM substrates, leading to the events of DNA damage response. PTM: Phosphorylated by ATM in response of ionizing radiation, and such phosphorylation is responsible intra-S phase checkpoint control and telomere maintenance. DISEASE: Defects in NBN are the cause of Nijmegen breakage syndrome (NBS) [MIM:251260]. NBS is an autosomal recessive syndrome characterized by chromosomal instability, radiation sensitivity, microcephaly, growth retardation, immunodeficiency and predisposition to cancer, particularly to lymphoid malignancies. DISEASE: Defects in NBN are a cause of susceptibility to breast cancer (BC) [MIM:114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. DISEASE: Defects in NBN may be associated with aplastic anemia (AA) [MIM:609135]. A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements. It is characterized by peripheral pancytopenia and marrow hypoplasia. DISEASE: Note=Defects in NBN might play a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL). MISCELLANEOUS: In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells. SIMILARITY: Contains 1 BRCT domain. SIMILARITY: Contains 1 FHA domain. SEQUENCE CAUTION: Sequence=AAI08651.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 550; Sequence=CAH56160.1; Type=Erroneous initiation; Note=Translation N-terminally extended; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/NBS1ID160.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NBN"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/nbs1/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on O60934
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
BX640816 - Homo sapiens mRNA; cDNA DKFZp686G19151 (from clone DKFZp686G19151). BC040519 - Homo sapiens cDNA clone IMAGE:4791579, containing frame-shift errors. AF051334 - Homo sapiens nibrin (NBS) mRNA, complete cds. BC146797 - Homo sapiens nibrin, mRNA (cDNA clone MGC:166968 IMAGE:8860301), complete cds. BC071590 - Homo sapiens cDNA clone IMAGE:30343504, containing frame-shift errors. AF058696 - Homo sapiens cell cycle regulatory protein p95 (NBS1) mRNA, complete cds. BC136802 - Homo sapiens nibrin, mRNA (cDNA clone MGC:168415 IMAGE:9020792), complete cds. BC136803 - Homo sapiens nibrin, mRNA (cDNA clone MGC:168416 IMAGE:9020793), complete cds. BC144413 - Homo sapiens cDNA clone IMAGE:9052934. AK289848 - Homo sapiens cDNA FLJ78201 complete cds, highly similar to Homo sapiens cell cycle regulatory protein p95 (NBS1) mRNA. AK223256 - Homo sapiens mRNA for nibrin variant, clone: SYN01540. AK312410 - Homo sapiens cDNA, FLJ92745, Homo sapiens Nijmegen breakage syndrome 1 (nibrin) (NBS1), mRNA. BC143065 - Synthetic construct Homo sapiens clone IMAGE:100000683, MGC:167276 nibrin (NBN) mRNA, encodes complete protein. BC143066 - Synthetic construct Homo sapiens clone IMAGE:100013542, MGC:167277 nibrin (NBN) mRNA, encodes complete protein. KJ897224 - Synthetic construct Homo sapiens clone ccsbBroadEn_06618 NBN gene, encodes complete protein. AB528582 - Synthetic construct DNA, clone: pF1KB0499, Homo sapiens NBN gene for nibrin, without stop codon, in Flexi system. AK001017 - Homo sapiens cDNA FLJ10155 fis, clone HEMBA1003433, highly similar to Homo sapiens gene for NBS1. JD124615 - Sequence 105639 from Patent EP1572962. JD294724 - Sequence 275748 from Patent EP1572962. JD300036 - Sequence 281060 from Patent EP1572962. JD377457 - Sequence 358481 from Patent EP1572962. JD268249 - Sequence 249273 from Patent EP1572962. JD296571 - Sequence 277595 from Patent EP1572962. JD360467 - Sequence 341491 from Patent EP1572962. JD492140 - Sequence 473164 from Patent EP1572962. JD491870 - Sequence 472894 from Patent EP1572962. JD237638 - Sequence 218662 from Patent EP1572962. JD349773 - Sequence 330797 from Patent EP1572962. JD130881 - Sequence 111905 from Patent EP1572962. JD501830 - Sequence 482854 from Patent EP1572962. BC108650 - Homo sapiens nibrin, mRNA (cDNA clone IMAGE:3918702), partial cds. BC005293 - Homo sapiens cDNA clone IMAGE:3997534. BC016762 - Homo sapiens nibrin, mRNA (cDNA clone IMAGE:4104186), partial cds. JD392526 - Sequence 373550 from Patent EP1572962. JD227821 - Sequence 208845 from Patent EP1572962. JD452409 - Sequence 433433 from Patent EP1572962. JD501355 - Sequence 482379 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_atmPathway - ATM Signaling Pathway h_atrbrcaPathway - Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility
Reactome (by CSHL, EBI, and GO)
Protein O60934 (Reactome details) participates in the following event(s):
R-HSA-75174 Association of RAD50:MRE11A complex with NBN (NBS1) via MRE11A interaction R-HSA-5684006 KPNA2 translocates NBN to the nucleus R-HSA-5684008 NBN binds KPNA2 R-HSA-3785768 MRN complex binds DNA double strand breaks R-HSA-5682020 MRN complex binds shortened telomeres R-HSA-5687675 LIG3 ligates remaining SSBs in MMEJ R-HSA-5686410 BLM mediates dissolution of double Holliday junction R-HSA-5686657 ERCC1:XPF cleaves flaps generated by SSA R-HSA-5693589 D-loop dissociation and strand annealing R-HSA-5693599 Association of Ku heterodimer with ends of DNA double-strand break R-HSA-5687465 MRN complex binds RBBP8 R-HSA-5693612 MRN complex bound to DNA ends recruits ATM R-HSA-5682018 MRN complex bound to shortened telomeres recruits ATM R-HSA-5685838 CX3 complex binds D-loop structures R-HSA-5693620 D-loop formation mediated by PALB2, BRCA2 and RAD51 R-HSA-5682044 KAT5 acetylates ATM at DNA DSBs R-HSA-5693540 MRN activates ATM R-HSA-5693598 ATM phosphorylates NBN R-HSA-5687464 MRN and RBBP8 resect DNA DSBs in MMEJ R-HSA-6792712 KAT5 acetylates ATM at shortened telomeres R-HSA-5682026 MRN bound to shortened telomeres activates ATM R-HSA-5687484 PARP1 or PARP2, FEN1 and POLQ are recruited to MMEJ site R-HSA-5687673 MRN recruits LIG3:XRCC1 to MMEJ sites R-HSA-5687664 FEN1 cleaves displaced ssDNA flaps during MMEJ R-HSA-5684081 MRN complex binds CDK2 and RBBP8 R-HSA-5693602 ATM recognizes H2AFX-Nucleosomes R-HSA-5684071 RNF4 ubiquitinates MDC1 R-HSA-5693593 D-loop extension by DNA polymerases R-HSA-5693584 Cleavage of Holliday junctions by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2) R-HSA-5686440 MUS81:EME1,EME2 cleaves D-loop R-HSA-5687640 POLQ extends annealed 3'-ssDNA overhangs in MMEJ R-HSA-5687653 PARP1,PARP2 dimers bound to MMEJ sites autoPARylate R-HSA-5693583 MDC1 associates with gamma-H2AFX at nuclear foci R-HSA-5683967 EYA1-4 dephosphorylates tyrosine Y142 of H2AFX R-HSA-5683986 APBB1 and MAPK8 bind diphosphorylated H2AFX R-HSA-5693549 ATM phosphorylates histone H2AFX on S139 at DNA DSBs R-HSA-5684096 CDK2 phosphorylates RBBP8 R-HSA-5684140 ATM phosphorylates RBBP8 R-HSA-5693608 Initial resection of double-strand break ends R-HSA-5684108 BRCA1 binds phosphorylated RBBP8 R-HSA-5693542 Association of RPA complexes with ssDNA at resected DNA DSBs R-HSA-5685994 Long-range resection of DNA DSBs by EXO1 or DNA2 R-HSA-5685341 BCDX2 complex stabilizes RAD51 filament R-HSA-5693561 RAD51 binds BRCA2 at resected DNA DSBs R-HSA-5685985 EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment R-HSA-5682967 WHSC1 binds DNA DSBs R-HSA-5693536 ATM phosphorylates MDC1 R-HSA-5683964 ATM phosphorylates EYA1-4 R-HSA-5684875 Binding of ATR:ATRIP to RPA at resected DNA DSBs R-HSA-5682983 ATM phosphorylates WHSC1 R-HSA-5682965 WHSC1 dimethylates histone H4 on lysine K21 at DSBs R-HSA-5682992 KDM4A,B bind H4K20Me2 R-HSA-5685011 ATR activation at DNA DSBs R-HSA-5684887 Activation of CHEK1 at resected DNA DSBs R-HSA-5684882 CHEK1 is recruited to resected DNA DSBs R-HSA-5693580 Association of RAD52 with the RPA complex at resected DNA DSBs R-HSA-5685156 ATR phosphorylates RPA2 R-HSA-5682588 RNF8 binds phosphorylated MDC1 at DNA DSBs R-HSA-5693566 TP53BP1 associates with H4K20Me2 at DNA DSBs R-HSA-5683077 RNF8 and RNF168 ubiquitinate KDM4A,B R-HSA-5693564 Association of RAD51 with RAD52:DNA double-strand break ends R-HSA-5682586 HERC2 and PIAS4 are recruited to DNA DSBs R-HSA-5682629 HERC2 facilitates UBE2N:UBE2V2 binding to RNF8 R-HSA-5682607 PIAS4 SUMOylates HERC2 with SUMO1 at DNA DSBs R-HSA-5682863 RNF168 binds DNA DSBs R-HSA-5682858 RNF8 and RNF168 ubiquitinate H2AFX R-HSA-5683384 UIMC1 and FAM175A bind DNA DSBs R-HSA-5683405 PPP5C dephosphorylates TP53BP1 R-HSA-5683425 ATM phosphorylates TP53BP1 at DNA DSBs R-HSA-6799332 ATR phosphorylates TP53 R-HSA-5686642 RAD52 promotes single strand annealing at resected DNA DSBs R-HSA-5682598 ATM phosphorylates HERC2 R-HSA-5693551 Phosphorylation of BRCA1-A complex at multiple sites by ATM R-HSA-5683385 Formation of BRCA1-A complex at DNA DSBs R-HSA-5683735 CHEK2 is recruited to DNA DSBs R-HSA-5683801 CHEK2 phosphorylates BRCA1 R-HSA-69891 Phosphorylation and activation of CHEK2 by ATM R-HSA-5684052 PIAS4 SUMOylates MDC1 R-HSA-5686685 RIF1 and PAX1IP bind TP53BP1 at DNA DSBs R-HSA-5686900 TP53BP1 recruits DCLRE1C to ATM R-HSA-5686704 Activated ATM phosphorylates DCLRE1C R-HSA-5693548 Sensing of DNA Double Strand Breaks R-HSA-2559586 DNA Damage/Telomere Stress Induced Senescence R-HSA-5685939 HDR through MMEJ (alt-NHEJ) R-HSA-5693606 DNA Double Strand Break Response R-HSA-5693568 Resolution of D-loop Structures through Holliday Junction Intermediates R-HSA-5685938 HDR through Single Strand Annealing (SSA) R-HSA-5693554 Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) R-HSA-5693571 Nonhomologous End-Joining (NHEJ) R-HSA-2559583 Cellular Senescence R-HSA-5693538 Homology Directed Repair R-HSA-5693532 DNA Double-Strand Break Repair R-HSA-5693579 Homologous DNA Pairing and Strand Exchange R-HSA-5693537 Resolution of D-Loop Structures R-HSA-5693567 HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA) R-HSA-912446 Meiotic recombination R-HSA-5693565 Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks R-HSA-2262752 Cellular responses to stress R-HSA-73894 DNA Repair R-HSA-5693607 Processing of DNA double-strand break ends R-HSA-5685942 HDR through Homologous Recombination (HRR) R-HSA-1500620 Meiosis R-HSA-8953897 Cellular responses to external stimuli R-HSA-5693616 Presynaptic phase of homologous DNA pairing and strand exchange R-HSA-1474165 Reproduction R-HSA-1640170 Cell Cycle R-HSA-69473 G2/M DNA damage checkpoint R-HSA-6804756 Regulation of TP53 Activity through Phosphorylation R-HSA-69481 G2/M Checkpoints R-HSA-5633007 Regulation of TP53 Activity R-HSA-69620 Cell Cycle Checkpoints R-HSA-3700989 Transcriptional Regulation by TP53 R-HSA-212436 Generic Transcription Pathway R-HSA-73857 RNA Polymerase II Transcription R-HSA-74160 Gene expression (Transcription)
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
