Nibrin

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Nibrin
Identifiers
Symbols NBN ; AT-V1; AT-V2; ATV; NBS; NBS1; P95
External IDs OMIM602667 MGI1351625 HomoloGene1858 GeneCards: NBN Gene
RNA expression pattern
PBB GE NBN 202907 s at tn.png
PBB GE NBN 202905 x at tn.png
PBB GE NBN 202906 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4683 27354
Ensembl ENSG00000104320 ENSMUSG00000028224
UniProt O60934 Q9R207
RefSeq (mRNA) NM_001024688 NM_013752
RefSeq (protein) NP_001019859 NP_038780
Location (UCSC) Chr 8:
89.93 – 90 Mb
Chr 4:
15.96 – 15.99 Mb
PubMed search [1] [2]

Nibrin, also known as NBN or Nbs1, is a protein which in humans is encoded by the NBN gene.[1][2][3]

Function[edit]

Nibrin is a protein associated with the repair of double strand breaks (DSBs) which pose serious damage to a genome. It is a 754 amino acid protein identified as a member of the NBS1/hMre11/RAD50(N/M/R, more commonly referred to as MRN) double strand DNA break repair complex.[4] This complex recognizes DNA damage and rapidly relocates to DSB sites and forms nuclear foci. It also has a role in regulation of N/M/R (MRN) protein complex activity which includes end-processing of both physiological and mutagenic DNA double strand breaks (DSBs).[5]

Cellular response to DSBs[edit]

Cellular response is performed by damage sensors, effectors of lesion repair and signal transduction. The central role is carried out by ataxia telangiectasia mutated (ATM) by activating the DSB signaling cascade, phosphorylating downstream substrates such as histone H2AX and NBS1. NBS1 relocates to DSB sites by interaction of FHA/BRCT domains with phosphorylated histone H2AX. Once it interacts with nibrin c-terminal hMre11-binding domain, hMre11 and hRad50 relocate from the cytoplasm to the nucleus then to sites of DSBs. They finally relocate to N/M/R where they form the foci at the site of damage.[6]

Double strand breaks (DSBs)[edit]

DSBs occur during V(D)J recombination during early B and T cell development. This is at the point when the cells of the immune system are developing and the DSBs effect the development of lymphoid cells. DSBs also occur in immunoglobulin class switch in mature B cells.[5] More frequently, however, DSBs are caused by mutagenic agents like radiomimetic chemicals and ionizing radiation(IR).

DSB mutations[edit]

As mentioned, DSBs cause extreme damage to DNA. Mutations that cause defective repair of DSBs tend to accumulate un-repaired DSBs. One such mutation is associated with Nijmegen breakage syndrome (NBS), a radiation hyper-sensitive disease.[7] It is a rare inherited autosomal recessive condition of chrosomal instability. It has been linked to mutations within exons 6-10 in the NBS1 gene which results in a truncated protein.[5] Characteristics of NBS include microcephaly, cranial characteristics, growth retardation, impaired sexual maturation, immunodeficiency/recurring infections and a predisposition to cancer. This predisposition to cancer may be linked to the DSBs occurring at the development of lymphoid cells.

Fertility[edit]

Two adult siblings, both heterozygous for two particular NBS1 nonsense mutations displayed cellular sensitivity to radiation, chromosome instability and fertility defects, but not the developmental defects that are typically found in other NBS patients.[8] These individuals appear to be primarily defective in homologous recombination, a process that accurately repairs double-strand breaks, both in somatic cells and during meiosis.

Orthologs of NBS1 have been studied in mice[9] and the plant Arabidopsis.[10] NBS1 mutant mice display cellular radiation sensitivity and female mice are sterile due to oogenesis failure.[9] Studies of NBS1 mutants in Arabidopsis revealed that NBS1 has a role in recombination during early stages of meiosis.[10]

NBS1 over-expression in cancer[edit]

NBS1 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway.[11] NBS1 is over-expressed in some prostate cancers,[12] in head and neck cancer,[13] and in squamous cell carcinoma of the oral cavity.[14]

Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[15] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[15] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, NBS1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

Interactions[edit]

Nibrin has been shown to interact with:

References[edit]

  1. ^ "Entrez Gene: Nibrin". 
  2. ^ Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A (May 1998). "Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome". Cell 93 (3): 467–76. doi:10.1016/S0092-8674(00)81174-5. PMID 9590180. 
  3. ^ Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR, Hays L, Morgan WF, Petrini JH (May 1998). "The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response". Cell 93 (3): 477–86. doi:10.1016/S0092-8674(00)81175-7. PMID 9590181. 
  4. ^ "Atlas of Genetics and Cytogenetics in Oncology and Haematology - NBS1". Retrieved 2008-02-12. 
  5. ^ a b c "eMedicine - Nijmegen Breakage Syndrome". Retrieved 2008-02-12. 
  6. ^ Molecular Biology
  7. ^ Kobayashi J (2004). "Molecular mechanism of the recruitment of NBS1/hMRE11/hRAD50 complex to DNA double-strand breaks: NBS1 binds to gamma-H2AX through FHA/BRCT domain". J. Radiat. Res. 45 (4): 473–8. doi:10.1269/jrr.45.473. PMID 15635255. 
  8. ^ Warcoin M, Lespinasse J, Despouy G, Dubois d'Enghien C, Laugé A, Portnoï MF, Christin-Maitre S, Stoppa-Lyonnet D, Stern MH (2009). "Fertility defects revealing germline biallelic nonsense NBN mutations". Hum. Mutat. 30 (3): 424–30. doi:10.1002/humu.20904. PMID 19105185. 
  9. ^ a b Kang J, Bronson RT, Xu Y (2002). "Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair". EMBO J. 21 (6): 1447–55. doi:10.1093/emboj/21.6.1447. PMC 125926. PMID 11889050. 
  10. ^ a b Waterworth WM, Altun C, Armstrong SJ, Roberts N, Dean PJ, Young K, Weil CF, Bray CM, West CE (2007). "NBS1 is involved in DNA repair and plays a synergistic role with ATM in mediating meiotic homologous recombination in plants". Plant J. 52 (1): 41–52. doi:10.1111/j.1365-313X.2007.03220.x. PMID 17672843. 
  11. ^ Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis 6: e1697. doi:10.1038/cddis.2015.58. PMID 25789972. 
  12. ^ Berlin A, Lalonde E, Sykes J, Zafarana G, Chu KC, Ramnarine VR, Ishkanian A, Sendorek DH, Pasic I, Lam WL, Jurisica I, van der Kwast T, Milosevic M, Boutros PC, Bristow RG (2014). "NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer". Oncotarget 5 (22): 11081–90. PMC 4294365. PMID 25415046. 
  13. ^ Yang MH, Chiang WC, Chou TY, Chang SY, Chen PM, Teng SC, Wu KJ (2006). "Increased NBS1 expression is a marker of aggressive head and neck cancer and overexpression of NBS1 contributes to transformation". Clin. Cancer Res. 12 (2): 507–15. doi:10.1158/1078-0432.CCR-05-1231. PMID 16428493. 
  14. ^ Hsu DS, Chang SY, Liu CJ, Tzeng CH, Wu KJ, Kao JY, Yang MH (2010). "Identification of increased NBS1 expression as a prognostic marker of squamous cell carcinoma of the oral cavity". Cancer Sci. 101 (4): 1029–37. doi:10.1111/j.1349-7006.2009.01471.x. PMID 20175780. 
  15. ^ a b Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
  16. ^ a b c d Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (April 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. PMC 316544. PMID 10783165. 
  17. ^ Kim ST, Lim DS, Canman CE, Kastan MB (December 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806. 
  18. ^ Chiba N, Parvin JD (October 2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". J. Biol. Chem. 276 (42): 38549–54. doi:10.1074/jbc.M105227200. PMID 11504724. 
  19. ^ Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH (July 1999). "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response". Science 285 (5428): 747–50. doi:10.1126/science.285.5428.747. PMID 10426999. 
  20. ^ Kobayashi J, Tauchi H, Sakamoto S, Nakamura A, Morishima K, Matsuura S, Kobayashi T, Tamai K, Tanimoto K, Komatsu K (October 2002). "NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain". Curr. Biol. 12 (21): 1846–51. doi:10.1016/s0960-9822(02)01259-9. PMID 12419185. 
  21. ^ a b Cerosaletti KM, Concannon P (June 2003). "Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation". J. Biol. Chem. 278 (24): 21944–51. doi:10.1074/jbc.M211689200. PMID 12679336. 
  22. ^ a b Trujillo KM, Yuan SS, Lee EY, Sung P (August 1998). "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". J. Biol. Chem. 273 (34): 21447–50. doi:10.1074/jbc.273.34.21447. PMID 9705271. 
  23. ^ Matsuzaki K, Shinohara A, Shinohara M (May 2008). "Forkhead-associated domain of yeast Xrs2, a homolog of human Nbs1, promotes nonhomologous end joining through interaction with a ligase IV partner protein, Lif1". Genetics 179 (1): 213–25. doi:10.1534/genetics.107.079236. PMC 2390601. PMID 18458108. 
  24. ^ a b Desai-Mehta A, Cerosaletti KM, Concannon P (March 2001). "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Mol. Cell. Biol. 21 (6): 2184–91. doi:10.1128/MCB.21.6.2184-2191.2001. PMC 86852. PMID 11238951. 
  25. ^ Zhu XD, Küster B, Mann M, Petrini JH, de Lange T (July 2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nat. Genet. 25 (3): 347–52. doi:10.1038/77139. PMID 10888888. 

Further reading[edit]

  • Kobayashi J, Antoccia A, Tauchi H, Matsuura S, Komatsu K (2005). "NBS1 and its functional role in the DNA damage response.". DNA Repair (Amst.) 3 (8–9): 855–61. doi:10.1016/j.dnarep.2004.03.023. PMID 15279770. 
  • Digweed M, Sperling K (2005). "Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks". DNA Repair (Amst.) 3 (8–9): 1207–17. doi:10.1016/j.dnarep.2004.03.004. PMID 15279809. 
  • Matsuura S, Kobayashi J, Tauchi H, Komatsu K (2004). "Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex". Adv. Biophys. 38: 65–80. doi:10.1016/S0065-227X(04)80076-5. PMID 15493328. 
  • Zhang Y, Zhou J, Lim CU (2006). "The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control". Cell Res. 16 (1): 45–54. doi:10.1038/sj.cr.7310007. PMID 16467875. 

External links[edit]