Ku70 Explained

Ku70 is a protein that, in humans, is encoded by the XRCC6 gene.^[1]

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.^[2]

Ku was originally identified when patients with systemic lupus erythematosus were found to have high levels of autoantibodies to the protein.^[3]

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.^[4] Mutant mice deficient in Ku70 exhibit early aging.^[5] 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.^[6] (Also see DNA damage theory of aging.)

Clinical

A mutation in this gene has been described in a set of 24 families with autism.^[7] 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,^[8]
• CHEK1,^[9]
• CREBBP,
• GCN5L2,^[10]
• HOXC4,^[11]
• Ku80,^{[10] [12] [13] [14] [15]}
• MRE11A,^[16]
• NCOA6,^{[17] [18]}
• NCF4,^[19]
• PCNA,^{[20] [21]}
• PTTG1,^[22]
• RPA2,^[23]
• TERF2,^[15]
• TERT^[24]
• VAV1,^[25] and
• WRN.^{[26] [27]}

Further reading

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

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

Notes and References

1. Pace P, Mosedale G, Hodskinson MR, Rosado IV, Sivasubramaniam M, Patel KJ . Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway . Science . 329 . 5988 . 219–23 . Jul 2010 . 20538911 . 10.1126/science.1192277 . 2010Sci...329..219P . 206527645 . Ketan J. Patel .
2. Boulton SJ, Jackson SP . 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 . Mar 1998 . 9501103 . 1170529 . 10.1093/emboj/17.6.1819 .
3. Web site: Entrez Gene: XRCC6 X-ray repair complementing defective repair in Chinese hamster cells 6 (Ku autoantigen, 70kDa).
4. Gu Y, Jin S, Gao Y, Weaver DT, Alt FW . 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 . Jul 1997 . 9223317 . 21559 . 10.1073/pnas.94.15.8076. 1997PNAS...94.8076G . free .
5. Li H, Vogel H, Holcomb VB, Gu Y, Hasty P . Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer . Molecular and Cellular Biology . 27 . 23 . 8205–14 . Dec 2007 . 17875923 . 2169178 . 10.1128/MCB.00785-07 .
6. 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
7. Sjaarda CP, Wood S, McNaughton AJ, Taylor S, Hudson ML, Liu X, Guerin A, Ayub M . Exome sequencing identifies de novo splicing variant in XRCC6 in sporadic case of autism . Journal of Human Genetics . December 2019 . 65 . 3 . 287–296 . 31827253 . 10.1038/s10038-019-0707-0 . 209312195 .
8. Song K, Jung Y, Jung D, Lee I . Human Ku70 interacts with heterochromatin protein 1alpha . The Journal of Biological Chemistry . 276 . 11 . 8321–7 . Mar 2001 . 11112778 . 10.1074/jbc.M008779200 . free .
9. Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y . 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 . Aug 2003 . 12756247 . 10.1074/jbc.M301765200 . free .
10. Barlev NA, Poltoratsky V, Owen-Hughes T, Ying C, Liu L, Workman JL, Berger SL . 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 . Mar 1998 . 9488450 . 108848 . 10.1128/mcb.18.3.1349.
11. Schild-Poulter C, Pope L, Giffin W, Kochan JC, Ngsee JK, Traykova-Andonova M, Haché RJ . 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 . May 2001 . 11279128 . 10.1074/jbc.M100768200 . free .
12. Gell D, Jackson SP . Mapping of protein-protein interactions within the DNA-dependent protein kinase complex . Nucleic Acids Research . 27 . 17 . 3494–502 . Sep 1999 . 10446239 . 148593 . 10.1093/nar/27.17.3494 .
13. Yang CR, Yeh S, Leskov K, Odegaard E, Hsu HL, Chang C, Kinsella TJ, Chen DJ, Boothman DA . Isolation of Ku70-binding proteins (KUBs) . Nucleic Acids Research . 27 . 10 . 2165–74 . May 1999 . 10219089 . 148436 . 10.1093/nar/27.10.2165 .
14. Singleton BK, Torres-Arzayus MI, Rottinghaus ST, Taccioli GE, Jeggo PA . The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit . Molecular and Cellular Biology . 19 . 5 . 3267–77 . May 1999 . 10207052 . 84121 . 10.1128/mcb.19.5.3267.
15. Song K, Jung D, Jung Y, Lee SG, Lee I . Interaction of human Ku70 with TRF2 . FEBS Letters . 481 . 1 . 81–5 . Sep 2000 . 10984620 . 10.1016/S0014-5793(00)01958-X . free .
16. Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C . Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis . Nature Genetics . 23 . 2 . 194–8 . Oct 1999 . 10508516 . 10.1038/13821 . 13443404 .
17. Ko L, Cardona GR, Chin WW . 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 . May 2000 . 10823961 . 18584 . 10.1073/pnas.97.11.6212 . 2000PNAS...97.6212K . free .
18. Ko L, Chin WW . 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 . Mar 2003 . 12519782 . 10.1074/jbc.M209723200 . free .
19. Grandvaux N, Grizot S, Vignais PV, Dagher MC . The Ku70 autoantigen interacts with p40phox in B lymphocytes . Journal of Cell Science . 112 . 4 . 503–13 . Feb 1999 . 10.1242/jcs.112.4.503 . 9914162 .
20. Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T . 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 . Oct 2002 . 12171929 . 10.1074/jbc.M206194200 . free .
21. Balajee AS, Geard CR . 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 . Mar 2001 . 11239001 . 29758 . 10.1093/nar/29.6.1341 .
22. Romero F, Multon MC, Ramos-Morales F, Domínguez A, Bernal JA, Pintor-Toro JA, Tortolero M . Human securin, hPTTG, is associated with Ku heterodimer, the regulatory subunit of the DNA-dependent protein kinase . Nucleic Acids Research . 29 . 6 . 1300–7 . Mar 2001 . 11238996 . 29753 . 10.1093/nar/29.6.1300 .
23. Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y . 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 . Mar 1999 . 10064605 . 1171229 . 10.1093/emboj/18.5.1397 .
24. Chai W, Ford LP, Lenertz L, Wright WE, Shay JW . Human Ku70/80 associates physically with telomerase through interaction with hTERT . The Journal of Biological Chemistry . 277 . 49 . 47242–7 . Dec 2002 . 12377759 . 10.1074/jbc.M208542200 . free .
25. Romero F, Dargemont C, Pozo F, Reeves WH, Camonis J, Gisselbrecht S, Fischer S . p95vav associates with the nuclear protein Ku-70 . Molecular and Cellular Biology . 16 . 1 . 37–44 . Jan 1996 . 8524317 . 230976 . 10.1128/mcb.16.1.37.
26. Karmakar P, Snowden CM, Ramsden DA, Bohr VA . 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 . Aug 2002 . 12177300 . 134248 . 10.1093/nar/gkf482 .
27. Li B, Comai L . Functional interaction between Ku and the werner syndrome protein in DNA end processing . The Journal of Biological Chemistry . 275 . 37 . 28349–52 . Sep 2000 . 10880505 . 10.1074/jbc.C000289200 . free .