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; OMA:XRCC6 - orthologs
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 right testis left testis ventricular zone islet of Langerhans embryo ganglionic eminence Achilles tendon right adrenal gland thymus beta cell Top expressed in thymus otic placode saccule otic vesicle neural layer of retina tail of embryo epiblast ventricular zone genital tubercle right lobe of liver 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 heterodimeric protein made up of Ku70 and Ku80, which together form Ku. In humans, is encoded by the XRCC6 gene. ^{[5] [6]} Ku70 plays a critical role in the DNA repair, maintenance and many other cellular processes.

Function

Together, Ku70 and Ku80 make up the Ku heterodimer form a quasi-symmetric structure, which encircles the double-stranded DNA. The DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) of the DNA repair pathway. It is also required for V(D)J recombination, which utilizes the NHEJ pathway to promote antigen diversity in the mammalian immune system. Ku70 is key for sensing and responding to cytosolic DNA, which is essential for the indication of infection. ^{[7] [8]} Within the heterodimer, Ku70 specifically binds directly to broken ends of double-stranded DNA breaks, or DSBs. Then together, Ku70 and Ku80 will tightly form a ring-like structure around the DNA strand, preventing further degradation. These steps are essential for the success of non-homologous end joining. ^[8]

The Ku70 subunit is located proximal to the DNA end. The Ku70 homodimer will stably bind 50 bp dsDNA substrate-forming complexes, allowing the DSBs to successfully enter the heterodimer, Ku's, central cavity. The Ku70 and Ku80 subunits can be expressed individually, however no DNA binding was observed from these isolated subunits. ^[9] Lysine reside found in the Ku70 N-terminal domain is critical for the end processing functionality of the Ku heterodimer.

In addition to its role in NHEJ, Ku is also required for telomere length maintenance and subtelomeric gene silencing. ^[10]

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

Ku70 was also discovered to be an inhibitor of Bax-dependent signaling pathway. Suppression of Ku70 demonstrated the increase in Bax-dependent apoptosis. Interactions between Ku70 and Bax occurs in the C-terminus of Ku70 and the N-terminus of Bax. These specific interactions result in the cytosolic sequestration of Bax. ^[11]

Aging

Structure of the Ku protein, highlighting the Ku70 (light blue), Ku80 (dark blue), and DNA (purple) subunits. The DNA subunit fills the central cavity of the Ku heterodimer. The Ku70 and Ku80 heterodimer encircles the duplex DNA to carry out DNA repair functionality.

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. ^[12] Mutant mice deficient in Ku70 exhibit early aging. ^[13] 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. ^[14] (Also see DNA damage theory of aging.)

Clinical

A mutation in this gene has been described in a set of 24 families with autism. ^[15] While this is suggestive that this gene may play a role in the development of autism, further investigation is required.

Active site that is crucial for the functionality of Ku highlighted in red. 5' lyase activity and end processing of Ku is dependent on the lysine residue found on the Ku70 N-terminal domain (highlighted in red).

Recent studies demonstrate that Ku proteins, when exactly balanced have the ability to act as a tumor suppressor gene. However, if there is an over-expression of Ku, it may act an oncoprotein. The presence of Ku of NHEJ in tumors affect the response to radiotherapy or chemotherapy, demonstrating the possibility that Ku has the potential to be used as a means to overcome resistance in cancer treatments. ^[16]

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, ^[17]
• CHEK1, ^[18]
• CREBBP, ^[19]
• GCN5L2, ^[19]
• HOXC4, ^[20]
• Ku80, ^{[19] [21] [22] [23] [24]}
• MRE11A, ^[25]
• NCOA6, ^{[26] [27]}
• NCF4, ^[28]
• PCNA, ^{[29] [30]}
• PTTG1, ^[31]
• RPA2, ^[32]
• TERF2, ^[24]
• TERT ^[33]
• VAV1, ^[34] and
• WRN. ^{[35] [36]}

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 (July 2010). "Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway". Science. 329 (5988): 219–223. Bibcode:2010Sci...329..219P. doi:10.1126/science.1192277. PMID   20538911. S2CID   206527645.
7. Matz KM, Guzman RM, Goodman AG (2019). "The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders". Nucleic Acid Sensing and Immunity - Part B. International Review of Cell and Molecular Biology. Vol. 345. pp. 35–136. doi:10.1016/bs.ircmb.2018.08.002. ISBN   978-0-12-815981-1. PMC   6445394 . PMID   30904196.
8. Tang CK, Coban C, Akira S, Ishii KJ (2014). "Route to Discovering the Immunogenic Properties of DNA from TLR9 to Cytosolic DNA Sensors". Biological DNA Sensor. pp. 3–41. doi:10.1016/B978-0-12-404732-7.00001-0. ISBN   978-0-12-404732-7.
9. Zahid S, Seif El Dahan M, Iehl F, Fernandez-Varela P, Le Du MH, Ropars V, et al. (April 2021). "The Multifaceted Roles of Ku70/80". International Journal of Molecular Sciences. 22 (8): 4134. doi: 10.3390/ijms22084134 . PMC   8073936 . PMID   33923616.  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
10. Boulton SJ, Jackson SP (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): 1819–1828. doi:10.1093/emboj/17.6.1819. PMC   1170529 . PMID   9501103.
11. Er E, Oliver L, Cartron PF, Juin P, Manon S, Vallette FM (September 2006). "Mitochondria as the target of the pro-apoptotic protein Bax". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1757 (9–10): 1301–1311. doi:10.1016/j.bbabio.2006.05.032. PMID   16836974.
12. Gu Y, Jin S, Gao Y, Weaver DT, Alt FW (July 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): 8076–8081. Bibcode:1997PNAS...94.8076G. doi: 10.1073/pnas.94.15.8076 . PMC   21559 . PMID   9223317.
13. Li H, Vogel H, Holcomb VB, Gu Y, Hasty P (December 2007). "Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer". Molecular and Cellular Biology. 27 (23): 8205–8214. doi:10.1128/MCB.00785-07. PMC   2169178 . PMID   17875923.
14. Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). "Cancer and aging as consequences of un-repaired DNA damage". In Kimura H, Suzuki A (eds.). New Research on DNA Damage. Nova Science Publishers. pp. 1–47. ISBN   978-1-60456-581-2.
15. Sjaarda CP, Wood S, McNaughton AJ, Taylor S, Hudson ML, Liu X, et al. (March 2020). "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.
16. Gullo C, Au M, Feng G, Teoh G (April 2006). "The biology of Ku and its potential oncogenic role in cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1765 (2): 223–234. doi:10.1016/j.bbcan.2006.01.001. PMID   16480833.
17. Song K, Jung Y, Jung D, Lee I (March 2001). "Human Ku70 interacts with heterochromatin protein 1alpha". The Journal of Biological Chemistry. 276 (11): 8321–8327. doi: 10.1074/jbc.M008779200 . PMID   11112778.
18. Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y (August 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): 29940–29947. doi: 10.1074/jbc.M301765200 . PMID   12756247.
19. Barlev NA, Poltoratsky V, Owen-Hughes T, Ying C, Liu L, Workman JL, et al. (March 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): 1349–1358. doi:10.1128/mcb.18.3.1349. PMC   108848 . PMID   9488450.
20. Schild-Poulter C, Pope L, Giffin W, Kochan JC, Ngsee JK, Traykova-Andonova M, et al. (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): 16848–16856. doi: 10.1074/jbc.M100768200 . PMID   11279128.
21. Gell D, Jackson SP (September 1999). "Mapping of protein-protein interactions within the DNA-dependent protein kinase complex". Nucleic Acids Research. 27 (17): 3494–3502. doi:10.1093/nar/27.17.3494. PMC   148593 . PMID   10446239.
22. Yang CR, Yeh S, Leskov K, Odegaard E, Hsu HL, Chang C, et al. (May 1999). "Isolation of Ku70-binding proteins (KUBs)". Nucleic Acids Research. 27 (10): 2165–2174. doi:10.1093/nar/27.10.2165. PMC   148436 . PMID   10219089.
23. 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". Molecular and Cellular Biology. 19 (5): 3267–3277. doi:10.1128/mcb.19.5.3267. PMC   84121 . PMID   10207052.
24. Song K, Jung D, Jung Y, Lee SG, Lee I (September 2000). "Interaction of human Ku70 with TRF2". FEBS Letters. 481 (1): 81–85. Bibcode:2000FEBSL.481...81S. doi: 10.1016/S0014-5793(00)01958-X . PMID   10984620.
25. Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C (October 1999). "Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis". Nature Genetics. 23 (2): 194–198. doi:10.1038/13821. PMID   10508516. S2CID   13443404.
26. 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): 6212–6217. Bibcode:2000PNAS...97.6212K. doi: 10.1073/pnas.97.11.6212 . PMC   18584 . PMID   10823961.
27. Ko L, Chin WW (March 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): 11471–11479. doi: 10.1074/jbc.M209723200 . PMID   12519782.
28. Grandvaux N, Grizot S, Vignais PV, Dagher MC (February 1999). "The Ku70 autoantigen interacts with p40phox in B lymphocytes". Journal of Cell Science. 112 ( Pt 4) (4): 503–513. doi:10.1242/jcs.112.4.503. PMID   9914162.
29. Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T (October 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): 40362–40367. doi: 10.1074/jbc.M206194200 . PMID   12171929.
30. Balajee AS, Geard CR (March 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): 1341–1351. doi:10.1093/nar/29.6.1341. PMC   29758 . PMID   11239001.
31. Romero F, Multon MC, Ramos-Morales F, Domínguez A, Bernal JA, Pintor-Toro JA, et al. (March 2001). "Human securin, hPTTG, is associated with Ku heterodimer, the regulatory subunit of the DNA-dependent protein kinase". Nucleic Acids Research. 29 (6): 1300–1307. doi:10.1093/nar/29.6.1300. PMC   29753 . PMID   11238996.
32. Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y (March 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): 1397–1406. doi:10.1093/emboj/18.5.1397. PMC   1171229 . PMID   10064605.
33. Chai W, Ford LP, Lenertz L, Wright WE, Shay JW (December 2002). "Human Ku70/80 associates physically with telomerase through interaction with hTERT". The Journal of Biological Chemistry. 277 (49): 47242–47247. doi: 10.1074/jbc.M208542200 . PMID   12377759.
34. Romero F, Dargemont C, Pozo F, Reeves WH, Camonis J, Gisselbrecht S, et al. (January 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.
35. Karmakar P, Snowden CM, Ramsden DA, Bohr VA (August 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): 3583–3591. doi:10.1093/nar/gkf482. PMC   134248 . PMID   12177300.
36. Li B, Comai L (September 2000). "Functional interaction between Ku and the werner syndrome protein in DNA end processing". The Journal of Biological Chemistry. 275 (37): 28349–28352. doi: 10.1074/jbc.C000289200 . PMID   10880505.

Further reading

• Smider V, Chu G (June 1997). "The end-joining reaction in V(D)J recombination". Seminars in Immunology. 9 (3): 189–197. 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 (September 2002). "Dimerization, translocation and localization of Ku70 and Ku80 proteins". Journal of Radiation Research. 43 (3): 223–236. 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