Biology:Nibrin

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.[1][2][3]

Function

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

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)

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 affect 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

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

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

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 often over-expressed in prostate cancer,[12] in liver cancer,[13] in esophageal squamous cell carcinoma,[14] in non-small cell lung carcinoma, hepatoma, and esophageal cancer,[15] in head and neck cancer,[16] and in squamous cell carcinoma of the oral cavity.[17]

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).[citation needed] (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.[citation needed] (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.

Herpes virus

HSV-1 infects more than 90% of adults over the age of 50. Alphaherpesviruses alone can cause the host to have mild symptoms, but these viruses can be associated with severe disease when they are transferred to a new species. Humans can even pass and also get an HSV-1 infection from other primate species. However, because of evolutionary differences between primate species, only some species can pass HSV-1 in an interspecies interaction. Also, though HSV-1 transmission from humans to other species primates can occur, there is no known sustained transmission chains that have resulted from constant transmission. A study found that Nbs1 is the most diverged in DNA sequence in the MRN complex between different primate species and that there is a high degree of species specificity, causing variability in promotion of the HSV-1 life cycle. The same study found that Nbs1 interacts with HSV-1's ICP0 proteins in an area of structural disorder of the nibrin. This suggests that in general, viruses commonly interact in intrinsically disordered domains in host proteins. It is possible that there are differences in the mammalian genomes that create unique environments for the viruses. Host proteins that are specific to the species might determine how the viruses must adapt to be able to ignite an infection in a new species. The evolution of increased disorder in nibrin benefits the host in decreasing ICP0 interaction and virus hijack. Nbs1 may not be the only host protein that evolves this way.[18]

HSV-1-infection has been shown to result from the phosphorylation of Nbs1. It has been shown in studies that activation of the MRN complex and ATM biochemical cascade is consistent for a resulting HSV-1 infection. When there is an HSV-1 infection, the nucleus is reorganized causing the formation of RCs (replication compartments) where gene expression and DNA replication occurs. Proteins in the host used for DNA repair and damage response are needed for virus production. ICP8, which is a viral single-strand binding protein, is known to interact with several DNA repair proteins, such as Rad50, Mre11, BRG1, and DNA-PKcs. Ul12 and ICP8 viral proteins function together as a recombinase, possibly showing that while working with the host's recombination factors, work to form a concatemer by stimulating homologous recombination. These proteins may move the MRN complex towards the viral genome so it is able to promote homologous recombination, and to prevent non-homologous recombination as non-homologous recombination can have anti-viral effects. This possibly shows that the reaction between UL12 and MRN regulates the complex in a way that benefits the herpes virus.[19]

Interactions

Nibrin has been shown to interact with:


References

  1. ↑ "Entrez Gene: Nibrin". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4683. 
  2. ↑ "Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome". Cell 93 (3): 467–76. May 1998. doi:10.1016/S0092-8674(00)81174-5. PMID 9590180. 
  3. ↑ "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. May 1998. doi:10.1016/S0092-8674(00)81175-7. PMID 9590181. 
  4. ↑ "Atlas of Genetics and Cytogenetics in Oncology and Haematology - NBS1". http://atlasgeneticsoncology.org//Genes/NBS1ID160.html. 
  5. ↑ 5.0 5.1 5.2 "eMedicine - Nijmegen Breakage Syndrome". http://www.emedicine.com/DERM/topic725.htm. 
  6. ↑ "Molecular Biology". http://www.nijmegenbreakagesyndrome.net/molecularbiology.htm. 
  7. ↑ "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. 2004. doi:10.1269/jrr.45.473. PMID 15635255. Bibcode: 2004JRadR..45..473K. 
  8. ↑ "Fertility defects revealing germline biallelic nonsense NBN mutations". Hum. Mutat. 30 (3): 424–30. 2009. doi:10.1002/humu.20904. PMID 19105185. 
  9. ↑ 9.0 9.1 "Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair". EMBO J. 21 (6): 1447–55. 2002. doi:10.1093/emboj/21.6.1447. PMID 11889050. 
  10. ↑ 10.0 10.1 "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. 2007. doi:10.1111/j.1365-313X.2007.03220.x. PMID 17672843. 
  11. ↑ "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis 6 (3): e1697. 2015. doi:10.1038/cddis.2015.58. PMID 25789972. 
  12. ↑ "NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer". Oncotarget 5 (22): 11081–90. 2014. doi:10.18632/oncotarget.2404. PMID 25415046. 
  13. ↑ "Clinical significance of increased expression of Nijmegen breakage syndrome gene (NBS1) in human primary liver cancer". Hepatol Int 8 (2): 250–9. 2014. doi:10.1007/s12072-013-9500-x. PMID 26202506. 
  14. ↑ "Prognostic significance of NBS1 and Snail expression in esophageal squamous cell carcinoma". Ann. Surg. Oncol. 19 (Suppl 3): S549–57. 2012. doi:10.1245/s10434-011-2043-2. PMID 21881923. 
  15. ↑ "Overexpression of NBS1 contributes to transformation through the activation of phosphatidylinositol 3-kinase/Akt". J. Biol. Chem. 280 (37): 32505–11. 2005. doi:10.1074/jbc.M501449200. PMID 16036916. 
  16. ↑ "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. 2006. doi:10.1158/1078-0432.CCR-05-1231. PMID 16428493. 
  17. ↑ "Identification of increased NBS1 expression as a prognostic marker of squamous cell carcinoma of the oral cavity". Cancer Sci. 101 (4): 1029–37. 2010. doi:10.1111/j.1349-7006.2009.01471.x. PMID 20175780. 
  18. ↑ Dianne I. Lou, Eui Tae Kim, Nicholas R. Meyerson, Neha J. Pancholi, Kareem N. Mohni, David Enard, Dmitri A. Petrov, Sandra K. Weller, Matthew D. Weitzman, Sara L. Sawyer (August 2016). “An Intrinsically Disordered Region of the DNA Repair Protein Nbs1 Is a Species-Specific Barrier to Herpes Simplex Virus 1 in Primates.” Cell Host and Microbe. 20 (2): 179-88. https://dx.doi.org/10.1016/j.chom.2016.07.003
  19. ↑ Nandakumar Balasubramanian, Ping Bai, Gregory Buchek, George Korza and Sandra K. Weller (December 2010). “Physical Interaction between the Herpes Simplex Virus Type 1 Exonuclease, UL12, and the DNA Double-Strand Break-Sensing MRN Complex.” J. Virol. 84 (24): 12504-12514. https://dx.doi.org/10.1128/JVI.01506-10
  20. ↑ 20.0 20.1 20.2 20.3 "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. April 2000. doi:10.1101/gad.14.8.927. PMID 10783165. 
  21. ↑ "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. December 1999. doi:10.1074/jbc.274.53.37538. PMID 10608806. 
  22. ↑ "Redistribution of BRCA1 among four different protein complexes following replication blockage". J. Biol. Chem. 276 (42): 38549–54. October 2001. doi:10.1074/jbc.M105227200. PMID 11504724. 
  23. ↑ "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response". Science 285 (5428): 747–50. July 1999. doi:10.1126/science.285.5428.747. PMID 10426999. 
  24. ↑ "NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain". Curr. Biol. 12 (21): 1846–51. October 2002. doi:10.1016/s0960-9822(02)01259-9. PMID 12419185. 
  25. ↑ 25.0 25.1 "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. June 2003. doi:10.1074/jbc.M211689200. PMID 12679336. 
  26. ↑ 26.0 26.1 "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". J. Biol. Chem. 273 (34): 21447–50. August 1998. doi:10.1074/jbc.273.34.21447. PMID 9705271. 
  27. ↑ "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. May 2008. doi:10.1534/genetics.107.079236. PMID 18458108. 
  28. ↑ 28.0 28.1 "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Mol. Cell. Biol. 21 (6): 2184–91. March 2001. doi:10.1128/MCB.21.6.2184-2191.2001. PMID 11238951. 
  29. ↑ "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nat. Genet. 25 (3): 347–52. July 2000. doi:10.1038/77139. PMID 10888888. 

Further reading

External links



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