Ku80

Ku80はXRCC5遺伝子でコードされているタンパク質である。

Ku80はKu70とヘテロ二量体を形成して、DNA修復のための非相同末端結合（NHEJ）経路に必要なKu自己抗原となる。また、NHEJ経路を利用して哺乳類の免疫系の抗原多様性を増大させるV(D)J遺伝子再構成にも要求される。また、NHEJ経路が関与しない、テロメア長の維持とサブテロメア遺伝子サイレンシングにも不可欠な役割を果たす。

Kuは、全身性エリテマトーデスの患者がタンパク質に対して高レベルの自己抗体を持っていることが判明したときに最初に同定された。

別名

Ku70は、以下で記述するいくつかの別名でも呼ばれる。

ループスKu自己抗原タンパク質p80（Lupus Ku autoantigen protein p80）
ATP依存性DNAヘリカーゼ2サブユニット2（ATP-dependent DNA helicase 2 subunit 2）
X-ray repair complementing defective repair in Chinese hamster cells 5
X線修復交差補完タンパク質5（XRCC6: X-ray repair cross-complementing 5）

エピジェネティックな抑制

Ku80のタンパク質発現レベルは、それをコードする遺伝子XRCC5のプロモーター領域のエピジェネティックな高メチル化によって抑制される。非小細胞肺癌の原発腫瘍と近辺の正常な肺組織の87個のマッチドペアの研究では、腫瘍の25％がXRCC5遺伝子座でヘテロ接合性を失い、同様の割合の腫瘍がXRCC5のプロモーター領域の高メチル化を示した。Ku80の発現レベル低下は、mRNAの発現レベル低下およびXRCC5プロモーターの高メチル化と有意に相関しており、一方で遺伝子のヘテロ接合性欠失とは関連していなかった。

老化との関連

Ku80にホモ接合性欠陥がある変異マウスは、老化の早期発症を経験する。Ku80^-/-マウスは、加齢に関連した7つの病状を示し、寿命と体長を著しく減少させる。Ku^-/+ヘテロ接合マウスでKu80対立遺伝子が1つだけ失われると、出生後の成長は正常となるが、骨格筋の老化が加速する。ヒト、ウシ、及びマウスの研究では、Ku80の発現レベルは種間で劇的に異なり、これらのレベルが種の寿命と強く相関していることが示された。これらの結果は、野生型Ku70遺伝子によるDNA二本鎖切断を修復する能力の低下が早期老化を引き起こし、この遺伝子が寿命の保証に重要な役割を果たしていることを示唆する。

臨床

この遺伝子の稀少なマイクロサテライト多型は、さまざまな放射線感受性患者の発癌に関連する。

癌の抑制

一般に、DNA修復関連遺伝子の発現が不足すると発癌のリスクが高まる。Ku80及びKu70の発現の喪失は黒色腫の進行の初期段階と関連しており、Ku70及びKu80による調節不全は黒色腫の転移の拡散に関連していることが判明している。さらに、Ku80の低発現は、腺癌タイプの15％および扁平上皮細胞タイプの非小細胞肺癌の32％で見られ、これはXRCC5プロモーターの高メチル化と相関していた。

Ku80は、さまざまな癌においてエピジェネティックに抑制される26種類のDNA修復タンパク質の1つである。

相互作用分子

Ku80は以下の生体分子と相互作用する。

脚注

1 2 3 “Entrez Gene: XRCC5 X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining; Ku autoantigen, 80kDa)”. アメリカ国立生物工学情報センター (2021年6月2日). 2021年8月7日閲覧。
↑ Simon J. Boulton, Stephen P. Jackson (16 March 1998). “Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing”. The EMBO Journal 17 (6): 1819–28. doi:10.1093/emboj/17.6.1819. PMC 1170529. PMID 9501103.
1 2 3 Ming-Ni Lee, Ruo-Chia Tseng, Han-Shui Hsu, Jia-Yang Chen, Ching Tzao, William L Ho, Yi-Ching Wang (2007 Feb 1). “Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer”. Clinical Cancer Research 13 (3): 832–8. doi:10.1158/1078-0432.CCR-05-2694. PMID 17289874.
↑ Hannes Vogel, Dae-Sik Lim, Gerard Karsenty, Milton Finegold, and Paul Hasty (September 14, 1999). “Deletion of Ku86 causes early onset of senescence in mice”. PNAS 96 (19): 10770–5. doi:10.1073/pnas.96.19.10770. PMC 17958. PMID 10485901.
↑ Erwin Reiling, Martijn E. T. Dollé, Sameh A. Youssef, Moonsook Lee, Bhawani Nagarajah, Marianne Roodbergen, Piet de With, Alain de Bruin, Jan H. Hoeijmakers, Jan Vijg, Harry van Steeg, Paul Hasty (April 16, 2014). “The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency”. PLOS ONE 9 (4): e93568. doi:10.1371/journal.pone.0093568. PMC 3989187. PMID 24740260.
↑ Nathalie Didier, Christophe Hourdé, Helge Amthor, Giovanna Marazzi, David Sassoon (1 September 2012). “Loss of a single allele for Ku80 leads to progenitor dysfunction and accelerated aging in skeletal muscle”. EMBO Molecular Medicine 4 (9): 910–23. doi:10.1002/emmm.201101075. PMC 3491824. PMID 22915554.
↑ Antonello Lorenzini, F Brad Johnson, Anthony Oliver, Maria Tresini, Jasmine S Smith, Mona Hdeib, Christian Sell, Vincent J Cristofalo, Thomas D Stamato (Nov-Dec 2009). “Significant correlation of species longevity with DNA double strand break recognition but not with telomere length”. Mechanisms of Ageing and Development 130 (11–12): 784–92. doi:10.1016/j.mad.2009.10.004. PMC 2799038. PMID 19896964.
↑ Monika Korabiowska, Michael Tscherny, Jerzy Stachura, Hermann Berger, Carlos Cordon-Cardo, Ulrich Brinck (01 April 2002). “Differential expression of DNA nonhomologous end-joining proteins Ku70 and Ku80 in melanoma progression”. Modern Pathology 15 (4): 426–33. doi:10.1038/modpathol.3880542. PMID 11950917.
1 2 “Mapping of protein-protein interactions within the DNA-dependent protein kinase complex”. Nucleic Acids Research 27 (17): 3494–502. (1 September 1999). doi:10.1093/nar/27.17.3494. PMC 148593. PMID 10446239.
↑ “Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit”. Journal of Biological Chemistry 272 (40): 24763–6. (October 1997). doi:10.1074/jbc.272.40.24763. PMID 9312071.
1 2 3 “Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication”. Biochimica et Biophysica Acta 1578 (1–3): 59–72. (2002 Oct 11). doi:10.1016/s0167-4781(02)00497-9. PMID 12393188.
1 2 “Repression of GCN5 histone acetyltransferase activity via bromodomain-mediated binding and phosphorylation by the Ku-DNA-dependent protein kinase complex”. Molecular and Cellular Biology 18 (3): 1349–58. (01 Mar 1998). doi:10.1128/mcb.18.3.1349. PMC 108848. PMID 9488450.
↑ “Isolation of Ku70-binding proteins (KUBs)”. Nucleic Acids Research 27 (10): 2165–74. (1 May 1999). doi:10.1093/nar/27.10.2165. PMC 148436. PMID 10219089.
↑ “The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit”. Molecular and Cellular Biology 19 (5): 3267–77. (May 1999). doi:10.1128/mcb.19.5.3267. PMC 84121. PMID 10207052.
↑ “Interaction of human Ku70 with TRF2”. FEBS Letters 481 (1): 81–5. (2000 Sep 8). doi:10.1016/s0014-5793(00)01958-x. PMID 10984620.
↑ “Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator”. PNAS 97 (11): 6212–7. (May 23, 2000). doi:10.1073/pnas.97.11.6212. PMC 18584. PMID 10823961.
↑ “Nuclear receptor coactivator thyroid hormone receptor-binding protein (TRBP) interacts with and stimulates its associated DNA-dependent protein kinase”. Journal of Biological Chemistry 278 (13): 11471–9. (2003 Mar 28). doi:10.1074/jbc.M209723200. PMID 12519782.
↑ “A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein”. Journal of Biological Chemistry 277 (43): 40362–7. (25 October 2002). doi:10.1074/jbc.M206194200. PMID 12171929.
↑ “Chromatin-bound PCNA complex formation triggered by DNA damage occurs independent of the ATM gene product in human cells”. Nucleic Acids Research 29 (6): 1341–51. (2001 Mar 15). doi:10.1093/nar/29.6.1341. PMC 29758. PMID 11239001.
↑ “The binding of Ku antigen to homeodomain proteins promotes their phosphorylation by DNA-dependent protein kinase”. Journal of Biological Chemistry 276 (20): 16848–56. (2001 May 18). doi:10.1074/jbc.M100768200. PMID 11279128.
↑ “The human Rap1 protein complex and modulation of telomere length”. Journal of Biological Chemistry 279 (27): 28585–91. (July 02, 2004). doi:10.1074/jbc.M312913200. PMID 15100233.
↑ “Human Ku70/80 associates physically with telomerase through interaction with hTERT”. Journal of Biological Chemistry 277 (49): 47242–7. (2002 Dec 6). doi:10.1074/jbc.M208542200. PMID 12377759.
↑ “Interferon-alpha signaling promotes nucleus-to-cytoplasmic redistribution of p95Vav, and formation of a multisubunit complex involving Vav, Ku80, and Tyk2”. Biochemical and Biophysical Research Communications 267 (3): 692–6. (27 January 2000). doi:10.1006/bbrc.1999.1978. PMID 10673353.
↑ “Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus”. Nucleic Acids Research 30 (16): 3583–91. (2002 Aug 15). doi:10.1093/nar/gkf482. PMC 134248. PMID 12177300.
↑ “Functional interaction between Ku and the werner syndrome protein in DNA end processing”. Journal of Biological Chemistry 275 (37): 28349–52. (2000 Sep 15). doi:10.1074/jbc.C000289200. PMID 10880505.

参考文献

“Dimerization, translocation and localization of Ku70 and Ku80 proteins.”. J. Radiat. Res. 43 (3): 223–36. (2003). doi:10.1269/jrr.43.223. PMID 12518983.
“Assignment of a human DNA double-strand break repair gene (XRCC5) to chromosome 2.”. Genomics 13 (4): 1088–94. (1992). doi:10.1016/0888-7543(92)90023-L. PMID 1505945.
“Identification of proteins binding to interferon-inducible transcriptional enhancers in hematopoietic cells.”. J. Biol. Chem. 267 (7): 4533–40. (1992). PMID 1537839.
“Localization of a DNA repair gene (XRCC5) involved in double-strand-break rejoining to human chromosome 2.”. Proc. Natl. Acad. Sci. U.S.A. 89 (14): 6423–7. (1992). doi:10.1073/pnas.89.14.6423. PMC 49513. PMID 1631138.
“Purification and characterization of proximal sequence element-binding protein 1, a transcription activating protein related to Ku and TREF that binds the proximal sequence element of the human U1 promoter.”. J. Biol. Chem. 265 (29): 17911–20. (1990). PMID 2211668.
“The autoantigen Ku is indistinguishable from NF IV, a protein forming multimeric protein-DNA complexes.”. J. Exp. Med. 172 (4): 1049–54. (1990). doi:10.1084/jem.172.4.1049. PMC 2188621. PMID 2212941.
“Isolation and characterization of cDNA encoding the 80-kDa subunit protein of the human autoantigen Ku (p70/p80) recognized by autoantibodies from patients with scleroderma-polymyositis overlap syndrome.”. Proc. Natl. Acad. Sci. U.S.A. 87 (5): 1777–81. (1990). doi:10.1073/pnas.87.5.1777. PMC 53566. PMID 2308937.
“cDNA-derived amino acid sequence of the 86-kDa subunit of the Ku antigen.”. J. Biol. Chem. 264 (23): 13407–11. (1989). PMID 2760028.
“Purification of the sequence-specific transcription factor CTCBF, involved in the control of human collagen IV genes: subunits with homology to Ku antigen.”. EMBO J. 14 (4): 791–800. (1995). doi:10.1002/j.1460-2075.1995.tb07057.x. PMC 398145. PMID 7882982.
“Human DNA helicase II: a novel DNA unwinding enzyme identified as the Ku autoantigen.”. EMBO J. 13 (20): 4991–5001. (1994). doi:10.1002/j.1460-2075.1994.tb06826.x. PMC 395441. PMID 7957065.
“The 86-kDa subunit of autoantigen Ku is a somatostatin receptor regulating protein phosphatase-2A activity.”. J. Biol. Chem. 269 (26): 17464–8. (1994). PMID 8021251.
“DNA-dependent ATPase from HeLa cells is related to human Ku autoantigen.”. Biochemistry 33 (28): 8548–57. (1994). doi:10.1021/bi00194a021. PMID 8031790.
“Ku80: product of the XRCC5 gene and its role in DNA repair and V(D)J recombination.”. Science 265 (5177): 1442–5. (1994). doi:10.1126/science.8073286. PMID 8073286.
“Regional assignment of a human DNA repair gene (XRCC5) to 2q35 by X-ray hybrid mapping.”. Genomics 21 (2): 423–7. (1994). doi:10.1006/geno.1994.1287. PMID 8088837.
“Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.”. Gene 138 (1–2): 171–4. (1994). doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
“Lupus autoantigen Ku protein binds HIV-1 TAR RNA in vitro.”. Biochem. Biophys. Res. Commun. 196 (2): 935–42. (1993). doi:10.1006/bbrc.1993.2339. PMID 8240370.
“A YAC contig encompassing the XRCC5 (Ku80) DNA repair gene and complementation of defective cells by YAC protoplast fusion.”. Genomics 30 (2): 320–8. (1996). doi:10.1006/geno.1995.9871. PMID 8586433.
“Expression of human glucocorticoid receptor gene and interaction of nuclear proteins with the transcriptional control element.”. J. Biol. Chem. 271 (31): 18662–71. (1996). doi:10.1074/jbc.271.31.18662. PMID 8702520.
“KARP-1: a novel leucine zipper protein expressed from the Ku86 autoantigen locus is implicated in the control of DNA-dependent protein kinase activity.”. EMBO J. 16 (11): 3172–84. (1997). doi:10.1093/emboj/16.11.3172. PMC 1169935. PMID 9214634.
“Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit.”. J. Biol. Chem. 272 (40): 24763–6. (1997). doi:10.1074/jbc.272.40.24763. PMID 9312071.

外部リンク

PDBe-KB：PDBで利用可能なヒトX線修復交差補完タンパク質5（Ku80の別称）の構造情報を提供する。

[entrezB-1] 1 2 3 “Entrez Gene: XRCC5 X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining; Ku autoantigen, 80kDa)”. アメリカ国立生物工学情報センター (2021年6月2日). 2021年8月7日閲覧。

[pmid9501103-2] Simon J. Boulton, Stephen P. Jackson (16 March 1998). “Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing”. The EMBO Journal 17 (6): 1819–28. doi:10.1093/emboj/17.6.1819. PMC 1170529. PMID 9501103.

[Lee-3] 1 2 3 Ming-Ni Lee, Ruo-Chia Tseng, Han-Shui Hsu, Jia-Yang Chen, Ching Tzao, William L Ho, Yi-Ching Wang (2007 Feb 1). “Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer”. Clinical Cancer Research 13 (3): 832–8. doi:10.1158/1078-0432.CCR-05-2694. PMID 17289874.

[pmid10485901-4] Hannes Vogel, Dae-Sik Lim, Gerard Karsenty, Milton Finegold, and Paul Hasty (September 14, 1999). “Deletion of Ku86 causes early onset of senescence in mice”. PNAS 96 (19): 10770–5. doi:10.1073/pnas.96.19.10770. PMC 17958. PMID 10485901.

[pmid24740260-5] Erwin Reiling, Martijn E. T. Dollé, Sameh A. Youssef, Moonsook Lee, Bhawani Nagarajah, Marianne Roodbergen, Piet de With, Alain de Bruin, Jan H. Hoeijmakers, Jan Vijg, Harry van Steeg, Paul Hasty (April 16, 2014). “The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency”. PLOS ONE 9 (4): e93568. doi:10.1371/journal.pone.0093568. PMC 3989187. PMID 24740260.

[pmid22915554-6] Nathalie Didier, Christophe Hourdé, Helge Amthor, Giovanna Marazzi, David Sassoon (1 September 2012). “Loss of a single allele for Ku80 leads to progenitor dysfunction and accelerated aging in skeletal muscle”. EMBO Molecular Medicine 4 (9): 910–23. doi:10.1002/emmm.201101075. PMC 3491824. PMID 22915554.

[pmid19896964-7] Antonello Lorenzini, F Brad Johnson, Anthony Oliver, Maria Tresini, Jasmine S Smith, Mona Hdeib, Christian Sell, Vincent J Cristofalo, Thomas D Stamato (Nov-Dec 2009). “Significant correlation of species longevity with DNA double strand break recognition but not with telomere length”. Mechanisms of Ageing and Development 130 (11–12): 784–92. doi:10.1016/j.mad.2009.10.004. PMC 2799038. PMID 19896964.

[pmid11950917-8] Monika Korabiowska, Michael Tscherny, Jerzy Stachura, Hermann Berger, Carlos Cordon-Cardo, Ulrich Brinck (01 April 2002). “Differential expression of DNA nonhomologous end-joining proteins Ku70 and Ku80 in melanoma progression”. Modern Pathology 15 (4): 426–33. doi:10.1038/modpathol.3880542. PMID 11950917.

[pmid10446239-9] 1 2 “Mapping of protein-protein interactions within the DNA-dependent protein kinase complex”. Nucleic Acids Research 27 (17): 3494–502. (1 September 1999). doi:10.1093/nar/27.17.3494. PMC 148593. PMID 10446239.

[pmid9312071-10] “Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit”. Journal of Biological Chemistry 272 (40): 24763–6. (October 1997). doi:10.1074/jbc.272.40.24763. PMID 9312071.

[pmid12393188-11] 1 2 3 “Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication”. Biochimica et Biophysica Acta 1578 (1–3): 59–72. (2002 Oct 11). doi:10.1016/s0167-4781(02)00497-9. PMID 12393188.

[pmid9488450-12] 1 2 “Repression of GCN5 histone acetyltransferase activity via bromodomain-mediated binding and phosphorylation by the Ku-DNA-dependent protein kinase complex”. Molecular and Cellular Biology 18 (3): 1349–58. (01 Mar 1998). doi:10.1128/mcb.18.3.1349. PMC 108848. PMID 9488450.

[pmid10219089-13] “Isolation of Ku70-binding proteins (KUBs)”. Nucleic Acids Research 27 (10): 2165–74. (1 May 1999). doi:10.1093/nar/27.10.2165. PMC 148436. PMID 10219089.

[pmid10207052-14] “The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit”. Molecular and Cellular Biology 19 (5): 3267–77. (May 1999). doi:10.1128/mcb.19.5.3267. PMC 84121. PMID 10207052.

[pmid10984620-15] “Interaction of human Ku70 with TRF2”. FEBS Letters 481 (1): 81–5. (2000 Sep 8). doi:10.1016/s0014-5793(00)01958-x. PMID 10984620.

[pmid10823961-16] “Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator”. PNAS 97 (11): 6212–7. (May 23, 2000). doi:10.1073/pnas.97.11.6212. PMC 18584. PMID 10823961.

[pmid12519782-17] “Nuclear receptor coactivator thyroid hormone receptor-binding protein (TRBP) interacts with and stimulates its associated DNA-dependent protein kinase”. Journal of Biological Chemistry 278 (13): 11471–9. (2003 Mar 28). doi:10.1074/jbc.M209723200. PMID 12519782.

[pmid12171929-18] “A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein”. Journal of Biological Chemistry 277 (43): 40362–7. (25 October 2002). doi:10.1074/jbc.M206194200. PMID 12171929.

[pmid11239001-19] “Chromatin-bound PCNA complex formation triggered by DNA damage occurs independent of the ATM gene product in human cells”. Nucleic Acids Research 29 (6): 1341–51. (2001 Mar 15). doi:10.1093/nar/29.6.1341. PMC 29758. PMID 11239001.

[pmid11279128-20] “The binding of Ku antigen to homeodomain proteins promotes their phosphorylation by DNA-dependent protein kinase”. Journal of Biological Chemistry 276 (20): 16848–56. (2001 May 18). doi:10.1074/jbc.M100768200. PMID 11279128.

[pmid15100233-21] “The human Rap1 protein complex and modulation of telomere length”. Journal of Biological Chemistry 279 (27): 28585–91. (July 02, 2004). doi:10.1074/jbc.M312913200. PMID 15100233.

[pmid12377759-22] “Human Ku70/80 associates physically with telomerase through interaction with hTERT”. Journal of Biological Chemistry 277 (49): 47242–7. (2002 Dec 6). doi:10.1074/jbc.M208542200. PMID 12377759.

[pmid10673353-23] “Interferon-alpha signaling promotes nucleus-to-cytoplasmic redistribution of p95Vav, and formation of a multisubunit complex involving Vav, Ku80, and Tyk2”. Biochemical and Biophysical Research Communications 267 (3): 692–6. (27 January 2000). doi:10.1006/bbrc.1999.1978. PMID 10673353.

[pmid12177300-24] “Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus”. Nucleic Acids Research 30 (16): 3583–91. (2002 Aug 15). doi:10.1093/nar/gkf482. PMC 134248. PMID 12177300.

[pmid10880505-25] “Functional interaction between Ku and the werner syndrome protein in DNA end processing”. Journal of Biological Chemistry 275 (37): 28349–52. (2000 Sep 15). doi:10.1074/jbc.C000289200. PMID 10880505.