Ku70

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.{{cite book |doi=10.1016/bs.ircmb.2018.08.002 |chapter=The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders |title=Nucleic Acid Sensing and Immunity - Part B |series=International Review of Cell and Molecular Biology |date=2019 | vauthors = Matz KM, Guzman RM, Goodman AG |volume=345 |pages=35–136 |pmid=30904196 |pmc=6445394 |isbn=978-0-12-815981-1 }}{{cite book |doi=10.1016/B978-0-12-404732-7.00001-0 |chapter=Route to Discovering the Immunogenic Properties of DNA from TLR9 to Cytosolic DNA Sensors |title=Biological DNA Sensor |date=2014 | vauthors = Tang CK, Coban C, Akira S, Ishii KJ |pages=3–41 |isbn=978-0-12-404732-7 }}

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.

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.{{cite journal | vauthors = Zahid S, Seif El Dahan M, Iehl F, Fernandez-Varela P, Le Du MH, Ropars V, Charbonnier JB | title = The Multifaceted Roles of Ku70/80 | journal = International Journal of Molecular Sciences | volume = 22 | issue = 8 | pages = 4134 | date = April 2021 | pmid = 33923616 | doi = 10.3390/ijms22084134 | doi-access = free | pmc = 8073936 }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}} 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.{{cite journal | vauthors = Boulton SJ, Jackson SP | title = Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing | journal = The EMBO Journal | volume = 17 | issue = 6 | pages = 1819–1828 | date = March 1998 | pmid = 9501103 | pmc = 1170529 | doi = 10.1093/emboj/17.6.1819 }}

Ku was originally identified when patients with systemic lupus erythematosus were found to have high levels of autoantibodies to the protein.{{cite web | title = Entrez Gene: XRCC6 X-ray repair complementing defective repair in Chinese hamster cells 6 (Ku autoantigen, 70kDa)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2547}}

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.{{cite journal | vauthors = Er E, Oliver L, Cartron PF, Juin P, Manon S, Vallette FM | title = Mitochondria as the target of the pro-apoptotic protein Bax | journal = Biochimica et Biophysica Acta | volume = 1757 | issue = 9-10 | pages = 1301–1311 | date = September 2006 | pmid = 16836974 | doi = 10.1016/j.bbabio.2006.05.032 }}

File:WIKIPEDIA FINAL 1.png

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.{{cite journal | vauthors = Gu Y, Jin S, Gao Y, Weaver DT, Alt FW | title = Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 15 | pages = 8076–8081 | date = July 1997 | pmid = 9223317 | pmc = 21559 | doi = 10.1073/pnas.94.15.8076 | doi-access = free | bibcode = 1997PNAS...94.8076G }} Mutant mice deficient in Ku70 exhibit early aging.{{cite journal | vauthors = Li H, Vogel H, Holcomb VB, Gu Y, Hasty P | title = Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer | journal = Molecular and Cellular Biology | volume = 27 | issue = 23 | pages = 8205–8214 | date = December 2007 | pmid = 17875923 | pmc = 2169178 | doi = 10.1128/MCB.00785-07 }} 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.{{cite book | vauthors = Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K |chapter=Cancer and aging as consequences of un-repaired DNA damage |pages=1–47 | veditors = Kimura H, Suzuki A |title=New Research on DNA Damage |date=2008 |publisher=Nova Science Publishers |isbn=978-1-60456-581-2 }} (Also see DNA damage theory of aging.)

A mutation in this gene has been described in a set of 24 families with autism.{{cite journal | vauthors = Sjaarda CP, Wood S, McNaughton AJ, Taylor S, Hudson ML, Liu X, Guerin A, Ayub M | title = Exome sequencing identifies de novo splicing variant in XRCC6 in sporadic case of autism | journal = Journal of Human Genetics | volume = 65 | issue = 3 | pages = 287–296 | date = March 2020 | pmid = 31827253 | doi = 10.1038/s10038-019-0707-0 | s2cid = 209312195 }} While this is suggestive that this gene may play a role in the development of autism, further investigation is required.

File:Wikipedia 2.2.png

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.{{cite journal | vauthors = Gullo C, Au M, Feng G, Teoh G | title = The biology of Ku and its potential oncogenic role in cancer | journal = Biochimica et Biophysica Acta | volume = 1765 | issue = 2 | pages = 223–234 | date = April 2006 | pmid = 16480833 | doi = 10.1016/j.bbcan.2006.01.001 }}

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)

Ku70 has been shown to interact with:

{{div col|colwidth=20em}}

• CBX5,{{cite journal | vauthors = Song K, Jung Y, Jung D, Lee I | title = Human Ku70 interacts with heterochromatin protein 1alpha | journal = The Journal of Biological Chemistry | volume = 276 | issue = 11 | pages = 8321–8327 | date = March 2001 | pmid = 11112778 | doi = 10.1074/jbc.M008779200 | doi-access = free }}
• CHEK1,{{cite journal | vauthors = Goudelock DM, Jiang K, Pereira E, Russell B, Sanchez Y | title = Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 29940–29947 | date = August 2003 | pmid = 12756247 | doi = 10.1074/jbc.M301765200 | doi-access = free }}
• CREBBP,
• GCN5L2,{{cite journal | vauthors = Barlev NA, Poltoratsky V, Owen-Hughes T, Ying C, Liu L, Workman JL, Berger SL | title = Repression of GCN5 histone acetyltransferase activity via bromodomain-mediated binding and phosphorylation by the Ku-DNA-dependent protein kinase complex | journal = Molecular and Cellular Biology | volume = 18 | issue = 3 | pages = 1349–1358 | date = March 1998 | pmid = 9488450 | pmc = 108848 | doi = 10.1128/mcb.18.3.1349 }}
• HOXC4,{{cite journal | vauthors = Schild-Poulter C, Pope L, Giffin W, Kochan JC, Ngsee JK, Traykova-Andonova M, Haché RJ | title = The binding of Ku antigen to homeodomain proteins promotes their phosphorylation by DNA-dependent protein kinase | journal = The Journal of Biological Chemistry | volume = 276 | issue = 20 | pages = 16848–16856 | date = May 2001 | pmid = 11279128 | doi = 10.1074/jbc.M100768200 | doi-access = free }}
• Ku80,{{cite journal | vauthors = Gell D, Jackson SP | title = Mapping of protein-protein interactions within the DNA-dependent protein kinase complex | journal = Nucleic Acids Research | volume = 27 | issue = 17 | pages = 3494–3502 | date = September 1999 | pmid = 10446239 | pmc = 148593 | doi = 10.1093/nar/27.17.3494 }}{{cite journal | vauthors = Yang CR, Yeh S, Leskov K, Odegaard E, Hsu HL, Chang C, Kinsella TJ, Chen DJ, Boothman DA | title = Isolation of Ku70-binding proteins (KUBs) | journal = Nucleic Acids Research | volume = 27 | issue = 10 | pages = 2165–2174 | date = May 1999 | pmid = 10219089 | pmc = 148436 | doi = 10.1093/nar/27.10.2165 }}{{cite journal | vauthors = Singleton BK, Torres-Arzayus MI, Rottinghaus ST, Taccioli GE, Jeggo PA | title = The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit | journal = Molecular and Cellular Biology | volume = 19 | issue = 5 | pages = 3267–3277 | date = May 1999 | pmid = 10207052 | pmc = 84121 | doi = 10.1128/mcb.19.5.3267 }}{{cite journal | vauthors = Song K, Jung D, Jung Y, Lee SG, Lee I | title = Interaction of human Ku70 with TRF2 | journal = FEBS Letters | volume = 481 | issue = 1 | pages = 81–85 | date = September 2000 | pmid = 10984620 | doi = 10.1016/S0014-5793(00)01958-X | doi-access = free | bibcode = 2000FEBSL.481...81S }}
• MRE11A,{{cite journal | vauthors = Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C | title = Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis | journal = Nature Genetics | volume = 23 | issue = 2 | pages = 194–198 | date = October 1999 | pmid = 10508516 | doi = 10.1038/13821 | s2cid = 13443404 }}
• NCOA6,{{cite journal | vauthors = Ko L, Cardona GR, Chin WW | title = Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 11 | pages = 6212–6217 | date = May 2000 | pmid = 10823961 | pmc = 18584 | doi = 10.1073/pnas.97.11.6212 | doi-access = free | bibcode = 2000PNAS...97.6212K }}{{cite journal | vauthors = Ko L, Chin WW | title = Nuclear receptor coactivator thyroid hormone receptor-binding protein (TRBP) interacts with and stimulates its associated DNA-dependent protein kinase | journal = The Journal of Biological Chemistry | volume = 278 | issue = 13 | pages = 11471–11479 | date = March 2003 | pmid = 12519782 | doi = 10.1074/jbc.M209723200 | doi-access = free }}
• NCF4,{{cite journal | vauthors = Grandvaux N, Grizot S, Vignais PV, Dagher MC | title = The Ku70 autoantigen interacts with p40phox in B lymphocytes | journal = Journal of Cell Science | volume = 112 ( Pt 4) | issue = 4 | pages = 503–513 | date = February 1999 | pmid = 9914162 | doi = 10.1242/jcs.112.4.503 }}
• PCNA,{{cite journal | vauthors = Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T | title = 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 = The Journal of Biological Chemistry | volume = 277 | issue = 43 | pages = 40362–40367 | date = October 2002 | pmid = 12171929 | doi = 10.1074/jbc.M206194200 | doi-access = free }}{{cite journal | vauthors = Balajee AS, Geard CR | title = Chromatin-bound PCNA complex formation triggered by DNA damage occurs independent of the ATM gene product in human cells | journal = Nucleic Acids Research | volume = 29 | issue = 6 | pages = 1341–1351 | date = March 2001 | pmid = 11239001 | pmc = 29758 | doi = 10.1093/nar/29.6.1341 }}
• PTTG1,{{cite journal | vauthors = Romero F, Multon MC, Ramos-Morales F, Domínguez A, Bernal JA, Pintor-Toro JA, Tortolero M | title = Human securin, hPTTG, is associated with Ku heterodimer, the regulatory subunit of the DNA-dependent protein kinase | journal = Nucleic Acids Research | volume = 29 | issue = 6 | pages = 1300–1307 | date = March 2001 | pmid = 11238996 | pmc = 29753 | doi = 10.1093/nar/29.6.1300 }}
• RPA2,{{cite journal | vauthors = Shao RG, Cao CX, Zhang H, Kohn KW, Wold MS, Pommier Y | title = Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes | journal = The EMBO Journal | volume = 18 | issue = 5 | pages = 1397–1406 | date = March 1999 | pmid = 10064605 | pmc = 1171229 | doi = 10.1093/emboj/18.5.1397 }}
• TERF2,
• TERT{{cite journal | vauthors = Chai W, Ford LP, Lenertz L, Wright WE, Shay JW | title = Human Ku70/80 associates physically with telomerase through interaction with hTERT | journal = The Journal of Biological Chemistry | volume = 277 | issue = 49 | pages = 47242–47247 | date = December 2002 | pmid = 12377759 | doi = 10.1074/jbc.M208542200 | doi-access = free }}
• VAV1,{{cite journal | vauthors = Romero F, Dargemont C, Pozo F, Reeves WH, Camonis J, Gisselbrecht S, Fischer S | title = p95vav associates with the nuclear protein Ku-70 | journal = Molecular and Cellular Biology | volume = 16 | issue = 1 | pages = 37–44 | date = January 1996 | pmid = 8524317 | pmc = 230976 | doi = 10.1128/mcb.16.1.37 }} and
• WRN.{{cite journal | vauthors = Karmakar P, Snowden CM, Ramsden DA, Bohr VA | title = Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus | journal = Nucleic Acids Research | volume = 30 | issue = 16 | pages = 3583–3591 | date = August 2002 | pmid = 12177300 | pmc = 134248 | doi = 10.1093/nar/gkf482 }}{{cite journal | vauthors = Li B, Comai L | title = Functional interaction between Ku and the werner syndrome protein in DNA end processing | journal = The Journal of Biological Chemistry | volume = 275 | issue = 37 | pages = 28349–28352 | date = September 2000 | pmid = 10880505 | doi = 10.1074/jbc.C000289200 | doi-access = free }}

{{Div col end}}

{{Clear}}

{{Reflist|33em}}

{{Refbegin|33em}}

• {{cite journal | vauthors = Smider V, Chu G | title = The end-joining reaction in V(D)J recombination | journal = Seminars in Immunology | volume = 9 | issue = 3 | pages = 189–197 | date = June 1997 | pmid = 9200330 | doi = 10.1006/smim.1997.0070 | doi-access = free }}
• {{cite journal | vauthors = Featherstone C, Jackson SP | title = Ku, a DNA repair protein with multiple cellular functions? | journal = Mutation Research | volume = 434 | issue = 1 | pages = 3–15 | date = May 1999 | pmid = 10377944 | doi = 10.1016/s0921-8777(99)00006-3 }}
• {{cite journal | vauthors = Koike M | title = Dimerization, translocation and localization of Ku70 and Ku80 proteins | journal = Journal of Radiation Research | volume = 43 | issue = 3 | pages = 223–236 | date = September 2002 | pmid = 12518983 | doi = 10.1269/jrr.43.223 | doi-access = free | bibcode = 2002JRadR..43..223K }}

{{Refend}}

• [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P12956 PDBe-KB] provides an overview of all the structure information available in the PDB for Human X-ray repair cross-complementing protein 6

{{PDB Gallery|geneid=2547}}