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FLASH GENE
Symbol NBN contributors: mct/pgu - updated : 07-01-2015
HGNC name nibrin
HGNC id 7652
Corresponding disease
NBS1 Nijmegen breakage syndrome
Location 8q21.3      Physical location : 90.945.563 - 90.996.899
Synonym name
  • p95 protein of the MRE11/RAD50 complex
  • Nijmegen breakage syndrome protein 1
  • cell cycle regulatory protein p95
  • Synonym symbol(s) ATV, MRN, ATV1, ATV2, P95, NBS1, AT-V1, AT-V2, FLJ10155, MGC87362, NBS
    DNA
    TYPE functioning gene
    STRUCTURE 51.34 kb     16 Exon(s)
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 - 4639 84 754 - 1998 9590181
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrinepancreas    
     thyroid   highly
    Lymphoid/Immunelymph node   highly
    Nervousbrainhindbraincerebellum  
     gangliasensory gangliadorsal root  
    Reproductivefemale systembreastmammary gland highly
    Urinarybladder   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Epithelialsecretoryglandularendocrine 
    Epithelialsecretoryglandularexocrine 
    Muscularstriatumskeletal  
    Nervouscentral   
    Nervousperipherous   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two globular domains at the N-terminus and forkhead associated domain (FHA)
  • two BRCT domain
  • MRE11-binding domain
  • a breast cancer BRCA1 C-terminal (BRCT) domain, implicated in protein-protein interactions, governing the access of activated ATM to SMC1A, required for induction of apoptosis by the MRE11 complex, and necessary for the DNA-double strand break (DSB) damage response
  • two domains found in cell cycle checkpoint proteins
  • both nuclear localizing signal (NLS) sequences and a nuclear export signal (NES) sequence
  • putative ATM phosphorylation site that is required for NBN relocalization to nucleoli in response to DNA damage
  • HOMOLOGY
    interspecies homolog to murine Nbn (71.9pc)
    Homologene
    FAMILY
  • MRE11/RD50 double strand break repair family
  • CATEGORY DNA associated
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm,nuclear bodies
    intracellular,nucleus,chromatin/chromosome
    intracellular,nucleus,nucleolus
    basic FUNCTION
  • involved in double-strand break repair by end joining (non homologous recombination) and cell-cycle checkpoint functions
  • acting as a major effector of ATM kinase
  • role in maintenance of telomeres and in tumor development
  • playing an essential role for viability of proliferating cells
  • playing a role in the repair of irradiation damage, maintenance of chromosomal stability and the recombination of Ig constant region genes in B lymphocytes
  • playing a role in cerebellar development
  • playing an active role in ATM activation beyond translocating Mre11/Rad50 to the nucleus and this function requires nibrin-ATM interaction
  • can regulate neuronal proliferation and neuroprotection via PI 3-kinase/Akt pathway while regulating neuronal differentiation in a different pathway
  • plays crucial roles in DNA damage response through its association with many proteins, including MRE11 and RAD50
  • overexpression inducing epithelial-mesenchymal transition through the upregulation of SNAIl expression, and co-expression of NBN/SNAI1 predicts metastasis in head and neck squamous cell carcinoma
  • nuclear export of nibrin may function, in part, to downregulate posttranslationally modified MRN complex components after DNA damage responses
  • its functions in both repair of V(D)J-generated DSBs and proliferation are essential for T-cell development
  • is one important target of RNF8 to regulate DNA DSB repair
  • ATM phosphorylation of NBN is required for the activation of the S-phase checkpoint
  • phosphorylation of NBN regulates its accumulation, and that of ATM, at sites of DNA DSB as well as the timing of the repair of these sites
  • plays unique and essential roles in ATM activation in response to DNA double-strand breaks
  • NBN and TOPBP1 have the potential to activate ATR independently, although both are required for functional activation of ATR
  • NBN and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair
  • NBN and ATM collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner
  • CELLULAR PROCESS cell cycle, checkpoint
    nucleotide, replication
    nucleotide, repair, recombination
    nucleotide, genomic integrity
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • chromosome instability pathway
  • pathway (NBN-HSF4-HSPA4/HSPA14 axis) to induce migration, invasion, and transformation, suggesting the activation of multiple signaling events induced by NBN overexpression
  • a component
  • member of the Mre11/Rad50(MRN) complex, double-strand break repair complex, exonuclease 3' to 5' and endonuclease activities in complex with RAD50 and MRE11A, NBN (called also nibrin), playing a crucial role in the DNA-double strand break (DNA-DSB) damage response
  • subunit of NBN binding directly to phosphorylated MDC1
  • BLM-DNA2-RPA-NBN and EXO1-BLM-RPA-NBN constitute two DNA end resection machineries for human DNA break repair
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • MRN complex required for ATR-dependent phosphorylation of structural maintenance of chromosomes 1 (SMC1L1), which acts within chromatin to ensure sister chromatid cohesion and to effect several DNA damage responses
  • interacting with MRE11
  • interaction with MDC1, required for proper control of the intra-S-phase checkpoint
  • interacting with RAD50 in a stable complex in absence of MRE11
  • cooperates with both ATM and H2AFX for regulation of ATM-dependent cell cycle checkpoint in response to DNA damage
  • binds to RAD18 after UV irradiation and mediates the recruitment of RAD18 to sites of DNA damage
  • SKP2-mediatetd NBN ubiquitination is a vital event for ATM activation in response to DNA damage
  • RBBP8 interacts with NBN and BRCA1, and connects CDK and ATM to regulate homologous recombination (HR)-mediated double-strand break repair
  • NBN-mediated mode of ATR activation is important for the repair of replication-associated DSBs
  • interaction of the E3 ubiquitin ligase RNF8 with NBN, a key regulator of DNA double-strand break (DSB) repair
  • specific domains of MTOR, RICTOR, or MAPKAP1 interacted with the internal domain (AA. 221-402) of NBN
  • DNMT1 function in the regulatory response is controlled by NBN
  • TCOF1-mediated NBN recruitment into the nucleoli regulates rRNA silencing in trans in the presence of distant chromosome breaks
  • interaction between the DDR factor NBN and TCOF1, a nucleolar protein that regulates ribosomal DNA (rDNA) transcription
  • NBN initiates POLH-dependent translesion DNA synthesis by recruiting RAD18 through its binding at the NBS1 C-terminus after UV exposure, and it also functions after the generation of interstrand crosslink DNA damage
  • cell & other
    REGULATION
    Other phosphorylated by ATM (role in DNA damage response)
    regulated by EP300(can regulate NBN-mediated DNA damage response, and these events occur in an acetylation-dependent manner)
    ASSOCIATED DISORDERS
    corresponding disease(s) NBS1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral germinal mutation      
    germinal mutation in acute lymphoblastic leukemia (ALL), and in non Hodgkin lymphoma
    tumoral   LOH    
    LOH in ovarian cancer and prostate carcinoma
    tumoral somatic mutation      
    mutation associated with aplastic anemia
    tumoral        
    chromosome instability in NBS1 heterozygotes
    tumoral     --over  
    contributes to transformation through the activation of PI3-kinase/Akt and to tumorigenesis
    tumoral     --over  
    is a prognostic marker of advanced head and neck squamous cell carcinoma
    constitutional germinal mutation      
    of the NES sequence in nibrin slowed the turnover of phosphorylated nibrin after irradiation
    constitutional   deletion    
    of the entire NBN protein in T-cell precursors results in severe lymphopenia and a hindrance to the double-negative 3 (DN3)-to-DN4 transition in early T-cell development, due to abnormal TCRB coding and signal joints as well as the functions of NBN in T-cell expansion
    tumoral germinal mutation     gain of function
    in patients with primary ovarian, fallopian tube, or peritoneal cancers
    tumoral     --over  
    increased in both MDS and AML, compared to controls
    constitutional       loss of function
    promotes genome instability by affecting DNA damage signaling pathway and impairing telomere integrity
    Susceptibility
  • to aplastic anemia
  • to inherited breast cancer susceptibility
  • Variant & Polymorphism other 657del5 deletion and perhaps the R215W substitution contribute to inherited breast cancer susceptibility
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS