The protein expression level of Ku80 can be repressed by epigenetic hypermethylation of the promoter region of gene XRCC5 which encodes Ku80. In a study of 87 matched pairs of primary tumors of non-small-cell lung carcinoma and nearby normal lung tissue, 25% of the tumors had loss of heterozygosity at the XRCC5 locus and a similar percentage of tumors had hypermethylation of the promoter region of XRCC5. Low protein expression of Ku80 was significantly associated with low mRNA expression and with XRCC5 promoter hypermethylation but not with LOH of the gene.
Mouse mutants with homozygous defects in Ku80 experience an early onset of senescence. Ku80(-/-) mice exhibit aging-related pathology (osteopenia, atrophic skin, hepatocellular degeneration, hepatocellular inclusions, hepatic hyperplastic foci and age-specific mortality). Furthermore, Ku80(-/-) mice exhibit severely reduced lifespan and size. Loss of only a single Ku80 allele in Ku(-/+) heterozygous mice causes accelerated aging in skeletal muscle, although post natal growth is normal. An analysis of the level of Ku80 protein in human, cow, and mouse indicated that Ku80 levels vary dramatically between species, and that these levels are strongly correlated with species longevity. These results suggest that the NHEJ pathway of DNA repair mediated by Ku80 plays a significant role in repairing double-strand breaks that would otherwise cause early senescence (see DNA damage theory of aging).
A deficiency in expression of a DNA repair gene increases the risk for cancer (see Deficient DNA repair in carcinogenesis). Ku80 protein expression was found to be deficient in melanoma. In addition, low expression of Ku80 was found in 15% of adenocarcinoma type and 32% of squamous cell type non-small cell lung cancers, and this was correlated with hypermethylation of the XRCC5 promoter.
Ku80 appears to be one of 26 different DNA repair proteins that are epigenetically repressed in various cancers (see Cancer epigenetics).
^Korabiowska M, Tscherny M, Stachura J, Berger H, Cordon-Cardo C, Brinck U (2002). "Differential expression of DNA nonhomologous end-joining proteins Ku70 and Ku80 in melanoma progression". Mod. Pathol. 15 (4): 426–33. doi:10.1038/modpathol.3880542. PMID11950917.
^Jin S, Kharbanda S, Mayer B, Kufe D, Weaver DT (October 1997). "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. doi:10.1074/jbc.272.40.24763. PMID9312071.
^ abcMatheos D, Ruiz MT, Price GB, Zannis-Hadjopoulos M (October 2002). "Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication". Biochim. Biophys. Acta. 1578 (1-3): 59–72. doi:10.1016/s0167-4781(02)00497-9. PMID12393188.
^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". J. Biol. Chem. 278 (13): 11471–9. doi:10.1074/jbc.M209723200. PMID12519782.
^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". J. Biol. Chem. 277 (43): 40362–7. doi:10.1074/jbc.M206194200. PMID12171929.
^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". J. Biol. Chem. 276 (20): 16848–56. doi:10.1074/jbc.M100768200. PMID11279128.
^O'Connor MS, Safari A, Liu D, Qin J, Songyang Z (July 2004). "The human Rap1 protein complex and modulation of telomere length". J. Biol. Chem. 279 (27): 28585–91. doi:10.1074/jbc.M312913200. PMID15100233.
^Chai W, Ford LP, Lenertz L, Wright WE, Shay JW (December 2002). "Human Ku70/80 associates physically with telomerase through interaction with hTERT". J. Biol. Chem. 277 (49): 47242–7. doi:10.1074/jbc.M208542200. PMID12377759.
^Adam L, Bandyopadhyay D, Kumar R (January 2000). "Interferon-alpha signaling promotes nucleus-to-cytoplasmic redistribution of p95Vav, and formation of a multisubunit complex involving Vav, Ku80, and Tyk2". Biochem. Biophys. Res. Commun. 267 (3): 692–6. doi:10.1006/bbrc.1999.1978. PMID10673353.
Chen DJ, Park MS, Campbell E, Oshimura M, Liu P, Zhao Y, White BF, Siciliano MJ (1992). "Assignment of a human DNA double-strand break repair gene (XRCC5) to chromosome 2". Genomics. 13 (4): 1088–94. doi:10.1016/0888-7543(92)90023-L. PMID1505945.
Wedrychowski A, Henzel W, Huston L, Paslidis N, Ellerson D, McRae M, Seong D, Howard OM, Deisseroth A (1992). "Identification of proteins binding to interferon-inducible transcriptional enhancers in hematopoietic cells". J. Biol. Chem. 267 (7): 4533–40. PMID1537839.
Knuth MW, Gunderson SI, Thompson NE, Strasheim LA, Burgess RR (1990). "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. PMID2211668.
Le Romancer M, Reyl-Desmars F, Cherifi Y, Pigeon C, Bottari S, Meyer O, Lewin MJ (1994). "The 86-kDa subunit of autoantigen Ku is a somatostatin receptor regulating protein phosphatase-2A activity". J. Biol. Chem. 269 (26): 17464–8. PMID8021251.
Cao QP, Pitt S, Leszyk J, Baril EF (1994). "DNA-dependent ATPase from HeLa cells is related to human Ku autoantigen". Biochemistry. 33 (28): 8548–57. doi:10.1021/bi00194a021. PMID8031790.
Taccioli GE, Gottlieb TM, Blunt T, Priestley A, Demengeot J, Mizuta R, Lehmann AR, Alt FW, Jackson SP, Jeggo PA (1994). "Ku80: product of the XRCC5 gene and its role in DNA repair and V(D)J recombination". Science. 265 (5177): 1442–5. doi:10.1126/science.8073286. PMID8073286.
Chen DJ, Marrone BL, Nguyen T, Stackhouse M, Zhao Y, Siciliano MJ (1994). "Regional assignment of a human DNA repair gene (XRCC5) to 2q35 by X-ray hybrid mapping". Genomics. 21 (2): 423–7. doi:10.1006/geno.1994.1287. PMID8088837.
Blunt T, Taccioli GE, Priestley A, Hafezparast M, McMillan T, Liu J, Cole CC, White J, Alt FW, Jackson SP (1996). "A YAC contig encompassing the XRCC5 (Ku80) DNA repair gene and complementation of defective cells by YAC protoplast fusion". Genomics. 30 (2): 320–8. doi:10.1006/geno.1995.9871. PMID8586433.
Warriar N, Pagé N, Govindan MV (1996). "Expression of human glucocorticoid receptor gene and interaction of nuclear proteins with the transcriptional control element". J. Biol. Chem. 271 (31): 18662–71. doi:10.1074/jbc.271.31.18662. PMID8702520.
Jin S, Kharbanda S, Mayer B, Kufe D, Weaver DT (1997). "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. doi:10.1074/jbc.272.40.24763. PMID9312071.