Ku70

XRCC6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1JEQ, 1JEY, 1JJR, 3RZX
Identifiers
Aliases	XRCC6 , X-ray repair complementing defective repair in Chinese hamster cells 6, CTC75, CTCBF, G22P1, KU70, ML8, TLAA, X-ray repair cross complementing 6
External IDs	OMIM: 152690 MGI: 95606 HomoloGene: 37483 GeneCards: XRCC6
Gene location (Human) Chr. Chromosome 22 (human) [1] Band 22q13.2 Start 41,621,163 bp [1] End 41,664,048 bp [1]
Gene location (Mouse) Chr. Chromosome 15 (mouse) [2] Band 15 E1|15 38.33 cM Start 81,872,036 bp [2] End 81,924,286 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans embryo ganglionic eminence Achilles tendon Right adrenal gland thymus smooth muscle tissue Left adrenal gland left uterine tube lymph node Top expressed in thymus otic placode saccule right lobe of liver primitive streak brown adipose tissue Paneth cell olfactory epithelium spermatid neural tube More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding double-stranded telomeric DNA binding telomeric DNA binding helicase activity 5'-deoxyribose-5-phosphate lyase activity DNA helicase activity protein C-terminus binding catalytic activity protein binding lyase activity hydrolase activity ATP binding DNA binding double-stranded DNA binding damaged DNA binding RNA binding cyclin binding protein-containing complex binding Cellular component cytosol nuclear telomere cap complex membrane transcription regulator complex chromosome nucleoplasm nonhomologous end joining complex nucleus Ku70:Ku80 complex cytoplasm extracellular region secretory granule lumen ficolin-1-rich granule lumen protein-DNA complex nucleolus protein-containing complex Biological process double-strand break repair via classical nonhomologous end joining protein heterotetramerization regulation of transcription, DNA-templated regulation of smooth muscle cell proliferation transcription, DNA-templated cellular response to DNA damage stimulus positive regulation of transcription, DNA-templated DNA ligation establishment of integrated proviral latency metabolism negative regulation of transcription, DNA-templated double-strand break repair via nonhomologous end joining telomere maintenance positive regulation of type I interferon production positive regulation of transcription by RNA polymerase II DNA duplex unwinding DNA repair cellular hyperosmotic salinity response brain development DNA recombination neutrophil degranulation cellular response to gamma radiation cellular response to X-ray positive regulation of protein kinase activity activation of innate immune response immune system process innate immune response Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2547 14375 Ensembl ENSG00000196419 ENSMUSG00000022471 UniProt P12956 P23475 RefSeq (mRNA) NM_001469 NM_001288976 NM_001288977 NM_001288978 NM_010247 RefSeq (protein) NP_001275905 NP_001275906 NP_001275907 NP_001460 NP_001275905.1 NP_001460.1 NP_034377 Location (UCSC) Chr 22: 41.62 – 41.66 Mb Chr 15: 81.87 – 81.92 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Ku70 is a protein that, in humans, is encoded by the XRCC6 gene. ^{[5] [6]}

Function

Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. It is also required for V(D)J recombination, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian immune system.

In addition to its role in NHEJ, Ku is also required for telomere length maintenance and subtelomeric gene silencing. ^[7]

Ku was originally identified when patients with systemic lupus erythematosus were found to have high levels of autoantibodies to the protein. ^[5]

Aging

Mouse embryonic stem cells with homozygous Ku70 mutations, that is Ku70^−/− cells, have markedly increased sensitivity to ionizing radiation compared to heterozygous Ku70^+/− or wild-type Ku70^+/+ embryonic stem cells. ^[8] Mutant mice deficient in Ku70 exhibit early aging. ^[9] Using several specific criteria of aging, the mutant mice were found to display the same aging signs as control mice, but at a considerably earlier chronological age. These results suggest that reduced ability to repair DNA double-strand breaks causes early aging, and that the wild-type Ku70 gene plays an important role in longevity assurance. ^[10] (Also see DNA damage theory of aging.)

Clinical

A mutation in this gene has been described in a set of 24 families with autism. ^[11] While this is suggestive that this gene may play a role in the development of autism, further investigation is required.

Nomenclature

Ku70 has been referred to by several names including:

• Lupus Ku autoantigen protein p70
• ATP-dependent DNA helicase 2 subunit 1
• X-ray repair complementing defective repair in Chinese hamster cells 6
• X-ray repair cross-complementing 6 (XRCC6)

Interactions

Ku70 has been shown to interact with:

• CBX5, ^[12]
• CHEK1, ^[13]
• CREBBP, ^[14]
• GCN5L2, ^[14]
• HOXC4, ^[15]
• Ku80, ^{[14] [16] [17] [18] [19]}
• MRE11A, ^[20]
• NCOA6, ^{[21] [22]}
• NCF4, ^[23]
• PCNA, ^{[24] [25]}
• PTTG1, ^[26]
• RPA2, ^[27]
• TERF2, ^[19]
• TERT ^[28]
• VAV1, ^[29] and
• WRN. ^{[30] [31]}

References

1. GRCh38: Ensembl release 89: ENSG00000196419 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022471 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: XRCC6 X-ray repair complementing defective repair in Chinese hamster cells 6 (Ku autoantigen, 70kDa)".
6. Pace P, Mosedale G, Hodskinson MR, Rosado IV, Sivasubramaniam M, Patel KJ (Jul 2010). "Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway". Science. 329 (5988): 219–23. Bibcode:2010Sci...329..219P. doi:10.1126/science.1192277. PMID   20538911. S2CID   206527645.
7. Boulton SJ, Jackson SP (Mar 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.
8. Gu Y, Jin S, Gao Y, Weaver DT, Alt FW (Jul 1997). "Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination". Proceedings of the National Academy of Sciences of the United States of America. 94 (15): 8076–81. Bibcode:1997PNAS...94.8076G. doi: 10.1073/pnas.94.15.8076 . PMC   21559 . PMID   9223317.
9. Li H, Vogel H, Holcomb VB, Gu Y, Hasty P (Dec 2007). "Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer". Molecular and Cellular Biology. 27 (23): 8205–14. doi:10.1128/MCB.00785-07. PMC   2169178 . PMID   17875923.
10. Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 Archived 2014-10-25 at the Wayback Machine ISBN   978-1604565812
11. Sjaarda CP, Wood S, McNaughton AJ, Taylor S, Hudson ML, Liu X, Guerin A, Ayub M (December 2019). "Exome sequencing identifies de novo splicing variant in XRCC6 in sporadic case of autism". Journal of Human Genetics. 65 (3): 287–296. doi:10.1038/s10038-019-0707-0. PMID   31827253. S2CID   209312195.
12. Song K, Jung Y, Jung D, Lee I (Mar 2001). "Human Ku70 interacts with heterochromatin protein 1alpha". The Journal of Biological Chemistry. 276 (11): 8321–7. doi: 10.1074/jbc.M008779200 . PMID   11112778.
13. Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y (Aug 2003). "Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex". The Journal of Biological Chemistry. 278 (32): 29940–7. doi: 10.1074/jbc.M301765200 . PMID   12756247.
14. Barlev NA, Poltoratsky V, Owen-Hughes T, Ying C, Liu L, Workman JL, Berger SL (Mar 1998). "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. doi:10.1128/mcb.18.3.1349. PMC   108848 . PMID   9488450.
15. Schild-Poulter C, Pope L, Giffin W, Kochan JC, Ngsee JK, Traykova-Andonova M, Haché RJ (May 2001). "The binding of Ku antigen to homeodomain proteins promotes their phosphorylation by DNA-dependent protein kinase". The Journal of Biological Chemistry. 276 (20): 16848–56. doi: 10.1074/jbc.M100768200 . PMID   11279128.
16. Gell D, Jackson SP (Sep 1999). "Mapping of protein-protein interactions within the DNA-dependent protein kinase complex". Nucleic Acids Research. 27 (17): 3494–502. doi:10.1093/nar/27.17.3494. PMC   148593 . PMID   10446239.
17. Yang CR, Yeh S, Leskov K, Odegaard E, Hsu HL, Chang C, Kinsella TJ, Chen DJ, Boothman DA (May 1999). "Isolation of Ku70-binding proteins (KUBs)". Nucleic Acids Research. 27 (10): 2165–74. doi:10.1093/nar/27.10.2165. PMC   148436 . PMID   10219089.
18. Singleton BK, Torres-Arzayus MI, Rottinghaus ST, Taccioli GE, Jeggo PA (May 1999). "The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit" (PDF). Molecular and Cellular Biology. 19 (5): 3267–77. doi:10.1128/mcb.19.5.3267. PMC   84121 . PMID   10207052.
19. Song K, Jung D, Jung Y, Lee SG, Lee I (Sep 2000). "Interaction of human Ku70 with TRF2". FEBS Letters. 481 (1): 81–5. doi: 10.1016/S0014-5793(00)01958-X . PMID   10984620.
20. Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C (Oct 1999). "Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis". Nature Genetics. 23 (2): 194–8. doi:10.1038/13821. PMID   10508516. S2CID   13443404.
21. Ko L, Cardona GR, Chin WW (May 2000). "Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 6212–7. Bibcode:2000PNAS...97.6212K. doi: 10.1073/pnas.97.11.6212 . PMC   18584 . PMID   10823961.
22. Ko L, Chin WW (Mar 2003). "Nuclear receptor coactivator thyroid hormone receptor-binding protein (TRBP) interacts with and stimulates its associated DNA-dependent protein kinase". The Journal of Biological Chemistry. 278 (13): 11471–9. doi: 10.1074/jbc.M209723200 . PMID   12519782.
23. Grandvaux N, Grizot S, Vignais PV, Dagher MC (Feb 1999). "The Ku70 autoantigen interacts with p40phox in B lymphocytes". Journal of Cell Science. 112 (4): 503–13. doi:10.1242/jcs.112.4.503. PMID   9914162.
24. Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T (Oct 2002). "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". The Journal of Biological Chemistry. 277 (43): 40362–7. doi: 10.1074/jbc.M206194200 . PMID   12171929.
25. Balajee AS, Geard CR (Mar 2001). "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. doi:10.1093/nar/29.6.1341. PMC   29758 . PMID   11239001.
26. Romero F, Multon MC, Ramos-Morales F, Domínguez A, Bernal JA, Pintor-Toro JA, Tortolero M (Mar 2001). "Human securin, hPTTG, is associated with Ku heterodimer, the regulatory subunit of the DNA-dependent protein kinase". Nucleic Acids Research. 29 (6): 1300–7. doi:10.1093/nar/29.6.1300. PMC   29753 . PMID   11238996.
27. Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y (Mar 1999). "Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes". The EMBO Journal. 18 (5): 1397–406. doi:10.1093/emboj/18.5.1397. PMC   1171229 . PMID   10064605.
28. Chai W, Ford LP, Lenertz L, Wright WE, Shay JW (Dec 2002). "Human Ku70/80 associates physically with telomerase through interaction with hTERT". The Journal of Biological Chemistry. 277 (49): 47242–7. doi: 10.1074/jbc.M208542200 . PMID   12377759.
29. Romero F, Dargemont C, Pozo F, Reeves WH, Camonis J, Gisselbrecht S, Fischer S (Jan 1996). "p95vav associates with the nuclear protein Ku-70". Molecular and Cellular Biology. 16 (1): 37–44. doi:10.1128/mcb.16.1.37. PMC   230976 . PMID   8524317.
30. Karmakar P, Snowden CM, Ramsden DA, Bohr VA (Aug 2002). "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. doi:10.1093/nar/gkf482. PMC   134248 . PMID   12177300.
31. Li B, Comai L (Sep 2000). "Functional interaction between Ku and the werner syndrome protein in DNA end processing". The Journal of Biological Chemistry. 275 (37): 28349–52. doi: 10.1074/jbc.C000289200 . PMID   10880505.

Further reading

• Smider V, Chu G (Jun 1997). "The end-joining reaction in V(D)J recombination". Seminars in Immunology. 9 (3): 189–97. doi:10.1006/smim.1997.0070. PMID   9200330.
• Featherstone C, Jackson SP (May 1999). "Ku, a DNA repair protein with multiple cellular functions?". Mutation Research. 434 (1): 3–15. doi:10.1016/s0921-8777(99)00006-3. PMID   10377944.
• Koike M (Sep 2002). "Dimerization, translocation and localization of Ku70 and Ku80 proteins". Journal of Radiation Research . 43 (3): 223–36. Bibcode:2002JRadR..43..223K. doi: 10.1269/jrr.43.223 . PMID   12518983.

External links

• PDBe-KB provides an overview of all the structure information available in the PDB for Human X-ray repair cross-complementing protein 6