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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/04/27 23:58:02」(JST)

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Nibrin, also known as NBN, 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 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

As mentioned, DSBs cause extreme damage to DNA. 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.

Interactions

Nibrin has been shown to interact with MRE11A,^[8]^[9]^[10]^[11]^[12] Ataxia telangiectasia mutated,^[8]^[13] Rad50,^[8]^[9]^[10]^[12] H2AFX,^[14] TERF2^[15] and BRCA1.^[8]^[16]^[17]

References

^ "Entrez Gene: Nibrin". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4683.
^ 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.
^ Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, 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.
^ "Atlas of Genetics and Cytogenetics in Oncology and Haematology - NBS1". http://atlasgeneticsoncology.org//Genes/NBS1ID160.html. Retrieved 2008-02-12.
^ ^a ^b ^c "eMedicine - Nijmegen Breakage Syndrome". http://www.emedicine.com/DERM/topic725.htm. Retrieved 2008-02-12.
^ Molecular Biology
^ 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.
^ ^a ^b ^c ^d Wang, Y; Cortez D, Yazdi P, Neff N, Elledge S J, Qin J (Apr. 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. (United States) 14 (8): 927–39. ISSN 0890-9369. . PMID 10783165. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=316544.
^ ^a ^b Cerosaletti, Karen M; Concannon Patrick (Jun. 2003). "Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation". J. Biol. Chem. (United States) 278 (24): 21944–51. doi:10.1074/jbc.M211689200. ISSN 0021-9258. PMID 12679336.
^ ^a ^b Trujillo, K M; Yuan S S, Lee E Y, Sung P (Aug. 1998). "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". J. Biol. Chem. (United States) 273 (34): 21447–50. doi:10.1074/jbc.273.34.21447. ISSN 0021-9258. PMID 9705271.
^ Matsuzaki, Kenichiro; Shinohara Akira, Shinohara Miki (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 (United States) 179 (1): 213–25. doi:10.1534/genetics.107.079236. ISSN 0016-6731. . PMID 18458108. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2390601.
^ ^a ^b Desai-Mehta, A; Cerosaletti K M, Concannon P (Mar. 2001). "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Mol. Cell. Biol. (United States) 21 (6): 2184–91. doi:10.1128/MCB.21.6.2184-2191.2001. ISSN 0270-7306. . PMID 11238951. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=86852.
^ Kim, S T; Lim D S, Canman C E, Kastan M B (Dec. 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. (United States) 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. ISSN 0021-9258. PMID 10608806.
^ Kobayashi, Junya; Tauchi Hiroshi, Sakamoto Shuichi, Nakamura Asako, Morishima Ken-ichi, Matsuura Shinya, Kobayashi Toshiko, Tamai Katsuyuki, Tanimoto Keiji, Komatsu Kenshi (Oct. 2002). "NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain". Curr. Biol. (England) 12 (21): 1846–51. doi:10.1016/S0960-9822(02)01259-9. ISSN 0960-9822. PMID 12419185.
^ Zhu, X D; Küster B, Mann M, Petrini J H, de Lange T (Jul. 2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nat. Genet. (United States) 25 (3): 347–52. doi:10.1038/77139. ISSN 1061-4036. PMID 10888888.
^ Chiba, N; Parvin J D (Oct. 2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". J. Biol. Chem. (United States) 276 (42): 38549–54. doi:10.1074/jbc.M105227200. ISSN 0021-9258. PMID 11504724.
^ Zhong, Q; Chen C F, Li S, Chen Y, Wang C C, Xiao J, Chen P L, Sharp Z D, Lee W H (Jul. 1999). "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response". Science (United States) 285 (5428): 747–50. doi:10.1126/science.285.5428.747. ISSN 0036-8075. PMID 10426999.

External links

GeneReviews/NCBI/NIH/UW entry on Nijmegen Breakage Syndrome
MeSH nibrin+protein,+human

UpToDate Contents

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1. ナイミーヘン染色体不安定症候群 nijmegen breakage syndrome

English Journal

Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways.

Keimling M, Volcic M, Csernok A, Wieland B, Dörk T, Wiesmüller L.Source3 Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, 89075 Ulm, Germany. lisa.wiesmueller@uni-ulm.de.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology.FASEB J.2011 Nov;25(11):3849-60. Epub 2011 Jul 21.
Ataxia telangiectasia mutated (ATM) has multiple functions in homologous recombination (HR) and nonhomologous end joining (NHEJ), which lead to conflicting data regarding its DNA double-strand break-repair (DSBR) functions in previous studies. To explore the effect of clinically relevant ATM mutatio
PMID 21778326

Anti-angiogenic effects of water extract of a formula consisting of Pulsatilla koreana, Panax ginseng and Glycyrrhiza uralensis.

Kim JM, Kim KS, Lee YW, Cho CK, Yoo HS, Bang JY, Kim EY, Kang IC.SourceEast-West Cancer Center, Dunsan Oriental Medical Hospital of Daejeon University, Daejeon, Korea.
Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine.Zhong Xi Yi Jie He Xue Bao.2011 Sep;9(9):1005-13.
OBJECTIVE: This study aimed to investigate the anti-angiogenic effects of the water extract of Pulsatilla koreana (Yabe ex Nakai) Nakai ex T. Mori., Panax ginseng C.A. Meyer and Glycyrrhiza uralensis Fisch (WEPPG).METHODS: The effects of WEPPG on fibroblast growth factor (bFGF)-induced angiogenesis
PMID 21906526

Japanese Journal

Induction of ATF3 by ionizing radiation is mediated via a signaling pathway that includes ATM, Nibrin1, stress-induced MAP kinases and ATF-2

KOOL J.
Oncogene 22, 4235-4242, 2003
NAID 30013807641

ATM-dependent phosphorylation of nibrin in response to radiation exposure.

GATEI M.
Nat Genet 25, 115-119, 2000
NAID 80011806306

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リンク元

「nib」

Nibrin
Identifiers
Symbols	NBN; AT-V1; AT-V2; ATV; NBS; NBS1; P95
External IDs	OMIM: 602667 MGI: 1351625 HomoloGene: 1858 GeneCards: NBN Gene
Gene Ontology
Molecular function	• damaged DNA binding; • ATP-dependent DNA helicase activity; • protein binding; • transcription factor binding; • protein N-terminus binding;
Cellular component	• nuclear chromosome, telomeric region; • intracellular; • nucleus; • nucleoplasm; • replication fork; • chromosome; • nucleolus; • Mre11 complex; • nuclear inclusion body;
Biological process	• DNA damage checkpoint; • telomere maintenance; • double-strand break repair via homologous recombination; • in utero embryonic development; • blastocyst growth; • DNA repair; • double-strand break repair; • double-strand break repair; • apoptotic process; • cell cycle; • cell cycle arrest; • mitotic cell cycle G2/M transition DNA damage checkpoint; • meiosis; • positive regulation of cell proliferation; • regulation of DNA-dependent DNA replication initiation; • DNA damage response, signal transduction by p53 class mediator; • mitotic cell cycle G1/S transition checkpoint; • G2/M transition checkpoint; • positive regulation of protein autophosphorylation; • DNA duplex unwinding; • positive regulation of kinase activity; • response to drug; • isotype switching; • negative regulation of neuron differentiation; • regulation of fibroblast proliferation; • neuromuscular process controlling balance;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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nib

アキシチニブ axitinib
ボスチニブ bosutinib
ブリバニブ brivanib
カネルチニブ canertinib
セジラニブ cediranib
ダサチニブ dasatinib　チロシンキナーゼ阻害薬　イマチニブ抵抗性の慢性骨髄性白血病、再発又は難治性のフィラデルフィア染色体陽性急性リンパ性白血病
エルロチニブ erlotinib
ゲフィチニブ gefitinib
イマチニブ imatinib　チロシンキナーゼ阻害薬　CML、CKIT(CD117)陽性消化管間質腫瘍、
ラパチニブ lapatinib
レスタウルチニブ lestaurtinib
リニファニブ linifanib
ロナファーニブ lonafarnib
ネラチニブ neratinib
ニブリン nibrin
ニロチニブ nilotinib　チロシンキナーゼ阻害薬　イマチニブ抵抗性の慢性期又は移行期の慢性骨髄性白血病
パゾパニブ pazopanib
ペガプタニブ pegaptanib
ラニビズマブ ranibizumab
セマキシニブ semaxinib
ソラフェニブ sorafenib
スニチニブ sunitinib　VEGFRやPDGFRチロシンキナーゼ阻害薬　イマチニブ抵抗性の消化管間質腫瘍、根治切除不能又は転移性の腎細胞癌
ティピファニブ tipifarnib
バンデタニブ vandetanib
バタラニブ vatalanib

[entrez-0] "Entrez Gene: Nibrin". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4683.

[pmid9590180-1] 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.

[pmid9590181-2] Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, 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.

[3] "Atlas of Genetics and Cytogenetics in Oncology and Haematology - NBS1". http://atlasgeneticsoncology.org//Genes/NBS1ID160.html. Retrieved 2008-02-12.

[eMed-4] "eMedicine - Nijmegen Breakage Syndrome". http://www.emedicine.com/DERM/topic725.htm. Retrieved 2008-02-12.

[5] Molecular Biology

[6] 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.

[pmid10783165-7] Wang, Y; Cortez D, Yazdi P, Neff N, Elledge S J, Qin J (Apr. 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. (United States) 14 (8): 927–39. ISSN 0890-9369. . PMID 10783165. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=316544.

[pmid12679336-8] Cerosaletti, Karen M; Concannon Patrick (Jun. 2003). "Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation". J. Biol. Chem. (United States) 278 (24): 21944–51. doi:10.1074/jbc.M211689200. ISSN 0021-9258. PMID 12679336.

[pmid9705271-9] Trujillo, K M; Yuan S S, Lee E Y, Sung P (Aug. 1998). "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". J. Biol. Chem. (United States) 273 (34): 21447–50. doi:10.1074/jbc.273.34.21447. ISSN 0021-9258. PMID 9705271.

[pmid18458108-10] Matsuzaki, Kenichiro; Shinohara Akira, Shinohara Miki (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 (United States) 179 (1): 213–25. doi:10.1534/genetics.107.079236. ISSN 0016-6731. . PMID 18458108. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2390601.

[pmid11238951-11] Desai-Mehta, A; Cerosaletti K M, Concannon P (Mar. 2001). "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Mol. Cell. Biol. (United States) 21 (6): 2184–91. doi:10.1128/MCB.21.6.2184-2191.2001. ISSN 0270-7306. . PMID 11238951. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=86852.

[pmid10608806-12] Kim, S T; Lim D S, Canman C E, Kastan M B (Dec. 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. (United States) 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. ISSN 0021-9258. PMID 10608806.

[pmid12419185-13] Kobayashi, Junya; Tauchi Hiroshi, Sakamoto Shuichi, Nakamura Asako, Morishima Ken-ichi, Matsuura Shinya, Kobayashi Toshiko, Tamai Katsuyuki, Tanimoto Keiji, Komatsu Kenshi (Oct. 2002). "NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain". Curr. Biol. (England) 12 (21): 1846–51. doi:10.1016/S0960-9822(02)01259-9. ISSN 0960-9822. PMID 12419185.

[pmid10888888-14] Zhu, X D; Küster B, Mann M, Petrini J H, de Lange T (Jul. 2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nat. Genet. (United States) 25 (3): 347–52. doi:10.1038/77139. ISSN 1061-4036. PMID 10888888.

[pmid11504724-15] Chiba, N; Parvin J D (Oct. 2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". J. Biol. Chem. (United States) 276 (42): 38549–54. doi:10.1074/jbc.M105227200. ISSN 0021-9258. PMID 11504724.

[pmid10426999-16] Zhong, Q; Chen C F, Li S, Chen Y, Wang C C, Xiao J, Chen P L, Sharp Z D, Lee W H (Jul. 1999). "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response". Science (United States) 285 (5428): 747–50. doi:10.1126/science.285.5428.747. ISSN 0036-8075. PMID 10426999.

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nibrin