The Ku heterodimer: Function in DNA repair and beyond

Mutation Research - Reviews in Mutation Research

Volumn 763, Issue , 2015, Pages 15-29

  Fell, Victoria L ^a   Schild Poulter, Caroline ^a  

^a ROBARTS RESEARCH INSTITUTE   (Canada)

Author keywords

Aging; Cancer; DNA repair; Ku; Non homologous end joining; Telomere

Indexed keywords

DOUBLE STRANDED DNA; HETERODIMER; KU ANTIGEN; KU HETERODIMER; SILENT INFORMATION REGULATOR PROTEIN; UNCLASSIFIED DRUG; CELL NUCLEUS ANTIGEN; DNA; DNA BINDING PROTEIN;

AMINO ACID SEQUENCE; ANIMAL MODEL; APOPTOSIS; CANCER INCIDENCE; CARBOXY TERMINAL SEQUENCE; CELL CYCLE CHECKPOINT; CELL CYCLE REGULATION; CRYSTAL STRUCTURE; DNA ALKYLATION; DNA BINDING; DNA DAMAGE; DNA END JOINING REPAIR; DNA REPAIR; DNA REPLICATION; DNA STRAND BREAKAGE; ENZYME ACTIVE SITE; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; IMMUNE RESPONSE; MOUSE; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; POSITION EFFECT; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN SUBUNIT; REVIEW; SENESCENCE; SILENCER ELEMENT; TELOMERE; TELOMERE HOMEOSTASIS; ANIMAL; CELL CYCLE; CHEMISTRY; DISEASES; GENETICS; METABOLISM;

EUKARYOTA; MAMMALIA; MUS; PROKARYOTA;

ANIMALS; ANTIGENS, NUCLEAR; APOPTOSIS; CELL CYCLE; DISEASE; DNA; DNA END-JOINING REPAIR; DNA-BINDING PROTEINS; HUMANS;

EID: 84925141081     PISSN: 13835742     EISSN: 13882139     Source Type: Journal    
DOI: 10.1016/j.mrrev.2014.06.002     Document Type: Review

References (253)

1. Mimori T., Akizuki M., Yamagata H., Inada S., Yoshida S., Homma M. Characterization of a high molecular weight acidic nuclear protein recognized by autoantibodies in sera from patients with polymyositis-scleroderma overlap. J. Clin. Invest. 1981, 68:611-620.
2. Mimori T. Clinical significance of anti-Ku autoantibodies--a serologic marker of overlap syndrome?. Intern. Med. 2002, 41:1096-1098.
3. Cooley H.M., Melny B.J., Gleeson R., Greco T., Kay T.W. Clinical and serological associations of anti-Ku antibody. J. Rheumatol. 1999, 26:563-567.
4. Takeda Y., Dynan W.S. Autoantibodies against DNA double-strand break repair proteins. Front. Biosci.: J. Virtual Lib. 2001, 6:D1412-D1422.
5. Mimori T., Hardin J.A., Steitz J.A. Characterization of the DNA-binding protein antigen Ku recognized by autoantibodies from patients with rheumatic disorders. J. Biol. Chem. 1986, 261:2274-2278.
6. de Vries E., van Driel W., Bergsma W.G., Arnberg A.C., van der Vliet P.C. HeLa nuclear protein recognizing DNA termini and translocating on DNA forming a regular DNA-multimeric protein complex. J. Mol. Biol. 1989, 208:65-78.
7. Griffith A.J., Blier P.R., Mimori T., Hardin J.A. Ku polypeptides synthesized in vitro assemble into complexes which recognize ends of double-stranded DNA. J. Biol. Chem. 1992, 267:331-338.
8. Getts R.C., Stamato T.D. Absence of a Ku-like DNA end binding activity in the xrs double-strand DNA repair-deficient mutant. J. Biol. Chem. 1994, 269:15981-15984.
9. Verhaegh G.W., Jongmans W., Morolli B., Jaspers N.G., van der Schans G.P., Lohman P.H., Zdzienicka M.Z. A novel type of X-ray-sensitive Chinese hamster cell mutant with radioresistant DNA synthesis and hampered DNA double-strand break repair. Mutat. Res. 1995, 337:119-129.
10. Taccioli G.E., Amatucci A.G., Beamish H.J., Gell D., Xiang X.H., Torres Arzayus M.I., Priestley A., Jackson S.P., Marshak Rothstein A., Jeggo P.A., Herrera V.L. Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity 1998, 9:355-366. 10.1016/S1074-7613(00)80618-4.
11. Rathmell W.K., Chu G. Involvement of the Ku autoantigen in the cellular response to DNA double-strand breaks. Proc. Natl. Acad. Sci. U. S. A. 1994, 91:7623-7627.
12. Rathmell W.K., Chu G. A DNA end-binding factor involved in double-strand break repair and V(D)J recombination. Mol. Cell. Biol. 1994, 14:4741-4748.
13. Smider V., Rathmell W.K., Lieber M.R., Chu G. Restoration of X-ray resistance and V(D)J recombination in mutant cells by Ku cDNA. Science 1994, 266:288-291.
14. Gu Y., Jin S., Gao Y., Weaver D.T., Alt F.W. Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination. Proc. Natl. Acad. Sci. U. S. A. 1997, 94:8076-8081.
15. Walker J.R., Corpina R.A., Goldberg J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 2001, 412:607-614. 10.1038/35088000.
16. Paillard S., Strauss F. Analysis of the mechanism of interaction of simian Ku protein with DNA. Nucleic Acids Res. 1991, 19:5619-5624. 10.1093/nar/19.20.5619.
17. Ono M., Tucker P.W., Capra J.D. Production and characterization of recombinant human Ku antigen. Nucleic Acids Res. 1994, 22:3918-3924.
18. Whittaker C.A., Hynes R.O. Distribution and evolution of von Willebrand/integrin A domains: widely dispersed domains with roles in cell adhesion and elsewhere. Mol. Biol. Cell 2002, 13:3369-3387. 10.1091/mbc.E02-05-0259.
19. Ribes-Zamora A., Mihalek I., Lichtarge O., Bertuch A.A. Distinct faces of the Ku heterodimer mediate DNA repair and telomeric functions. Nat. Struct. Mol. Biol. 2007, 14:301-307. 10.1038/nsmb1214.
20. Ribes-Zamora A., Indiviglio S.M., Mihalek I., Williams C.L., Bertuch A.A. TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres. Cell Rep. 2013, 10.1016/j.celrep.2013.08.040.
21. Fell V.L., Schild-Poulter C. Ku regulates signaling to DNA damage response pathways through the Ku70 von Willebrand A domain. Mol. Cell. Biol. 2012, 32:76-87. 10.1128/MCB. 05661-11.
22. Strande N., Roberts S.A., Oh S., Hendrickson E.A., Ramsden D.A. Specificity of the dRP/AP lyase of Ku promotes nonhomologous end joining (NHEJ) fidelity at damaged ends. J. Biol. Chem. 2012, 287:13686-13693. 10.1074/jbc.M111.329730.
23. Roberts S.A., Strande N., Burkhalter M.D., Strom C., Havener J.M., Hasty P., Ramsden D.A. Ku is a 5'-dRP/AP lyase that excises nucleotide damage near broken ends. Nature 2010, 464:1214-1217. 10.1038/nature08926.
24. Shirodkar P., Fenton A.L., Meng L., Koch C.A. Identification and functional characterization of a Ku-binding motif in aprataxin polynucleotide kinase/phosphatase-like factor (APLF). J. Biol. Chem. 2013, 288:19604-19613. 10.1074/jbc.M112.440388.
25. Gell D., Jackson S.P. Mapping of protein-protein interactions within the DNA-dependent protein kinase complex. Nucleic Acids Res. 1999, 27:3494-3502.
26. Singleton B.K., Torres-Arzayus M.I., Rottinghaus S.T., Taccioli G.E., Jeggo P.A. The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit. Mol. Cell. Biol. 1999, 19:3267-3277.
27. Aravind L., Koonin E.V. SAP - a putative DNA-binding motif involved in chromosomal organization. Trends Biochem. Sci. 2000, 25:112-114. 10.1016/S0968-0004(99)01537-6.
28. Hu S., Pluth J.M., Cucinotta F.A. Putative binding modes of Ku70-SAP domain with double strand DNA: a molecular modeling study. J. Mol. Model. 2012, 18:2163-2174. 10.1007/s00894-011-1234-x.
29. Wang J., Dong X., Reeves W.H. A model for Ku heterodimer assembly and interaction with DNA. Implications for the function of Ku antigen. J. Biol. Chem. 1998, 273:31068-31074.
30. Cohen H.Y., Lavu S., Bitterman K.J., Hekking B., Imahiyerobo T.A., Miller C., Frye R., Ploegh H., Kessler B.M., Sinclair D.A. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol. Cell 2004, 13:627-638. 10.1016/S1097-2765(04)00094-2.
31. Kim K.B., Kim D.W., Park J.W., Jeon Y.J., Kim D., Rhee S., Chae J.I., Seo S.B. Inhibition of Ku70 acetylation by INHAT subunit SET/TAF-Ibeta regulates Ku70-mediated DNA damage response. Cell. Mol. Life Sci.: CMLS 2013, 10.1007/s00018-013-1525-8.
32. Hang L.E., Lopez C.R., Liu X., Williams J.M., Chung I., Wei L., Bertuch A.A., Zhao X. Regulation of Ku-DNA association by Yku70 C-terminal tail and SUMO modification. J. Biol. Chem. 2014, 289:10308-10317. 10.1074/jbc.M113.526178.
33. Schild-Poulter C., Pope L., Giffin W., Kochan J.C., Ngsee J.K., Traykova-Andonova M., Hache R.J. The binding of Ku antigen to homeodomain proteins promotes their phosphorylation by DNA-dependent protein kinase. J. Biol. Chem. 2001, 276:16848-16856. 10.1074/jbc.M100768200.
34. Bertinato J., Schild-Poulter C., Hache R.J. Nuclear localization of Ku antigen is promoted independently by basic motifs in the Ku70 and Ku80 subunits. J. Cell Sci. 2001, 114:89-99.
35. Singleton B.K., Priestley A., Steingrimsdottir H., Gell D., Blunt T., Jackson S.P., Lehmann A.R., Jeggo P.A. Molecular and biochemical characterization of xrs mutants defective in Ku80. Mol. Cell. Biol. 1997, 17:1264-1273.
36. Errami A., Smider V., Rathmell W.K., He D.M., Hendrickson E.A., Zdzienicka M.Z., Chu G. Ku86 defines the genetic defect and restores X-ray resistance and V(D)J recombination to complementation group 5 hamster cell mutants. Mol. Cell. Biol. 1996, 16:1519-1526.
37. Downs J.A., Jackson S.P. A means to a DNA end: the many roles of Ku. Nat. Rev. Mol. Cell Biol. 2004, 5:367-378. 10.1038/nrm1367.
38. Doherty A.J., Jackson S.P., Weller G.R. Identification of bacterial homologues of the Ku DNA repair proteins. FEBS Lett. 2001, 500:186-188. 10.1016/S0014-5793(01)02589-3.
39. Aravind L., Koonin E.V. Prokaryotic homologs of the eukaryotic DNA-end-binding protein Ku, novel domains in the Ku protein and prediction of a prokaryotic double-strand break repair system. Genome Res. 2001, 11:1365-1374. 10.1101/gr.181001.
40. Bowater R., Doherty A.J. Making ends meet: repairing breaks in bacterial DNA by non-homologous end-joining. PLoS Genet. 2006, 2:e8. 10.1371/journal.pgen.0020008.
41. Weller G.R., Kysela B., Roy R., Tonkin L.M., Scanlan E., Della M., Devine S.K., Day J.P., Wilkinson A., d'Adda di Fagagna F., Devine K.M., Bowater R.P., Jeggo P.A., Jackson S.P., Doherty A.J. Identification of a DNA nonhomologous end-joining complex in bacteria. Science 2002, 297:1686-1689. 10.1126/science.1074584.
42. Frit P., Barboule N., Yuan Y., Gomez D., Calsou P. Alternative end-joining pathway(s): bricolage at DNA breaks. DNA Repair (Amst.) 2014, 17:81-97. 10.1016/j.dnarep.2014.02.007.
43. Deriano L., Roth D.B. Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. Annu. Rev. Genet. 2013, 47:433-455. 10.1146/annurev-genet-110711-155540.
44. Krejci L., Altmannova V., Spirek M., Zhao X. Homologous recombination and its regulation. Nucleic Acids Res. 2012, 40:5795-5818. 10.1093/nar/gks270.
45. Williams G.J., Hammel M., Radhakrishnan S.K., Ramsden D., Lees-Miller S.P., Tainer J.A. Structural insights into NHEJ: building up an integrated picture of the dynamic DSB repair super complex, one component and interaction at a time. DNA Repair (Amst.) 2014, 17:110-120. 10.1016/j.dnarep.2014.02.009.
46. Ochi T., Wu Q., Blundell T.L. The spatial organization of non-homologous end joining: from bridging to end joining. DNA Repair (Amst.) 2014, 17:98-109. 10.1016/j.dnarep.2014.02.010.
47. Grundy G.J., Moulding H.A., Caldecott K.W., Rulten S.L. One ring to bring them all - the role of Ku in mammalian non-homologous end joining. DNA Repair (Amst.) 2014, 17:30-38. 10.1016/j.dnarep.2014.02.019.
48. Boulton S.J., Jackson S.P. Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J. 1996, 15:5093-5103.
49. Chen S., Inamdar K.V., Pfeiffer P., Feldmann E., Hannah M.F., Yu Y., Lee J.W., Zhou T., Lees-Miller S.P., Povirk L.F. Accurate in vitro end joining of a DNA double strand break with partially cohesive 3'-overhangs and 3'-phosphoglycolate termini: effect of Ku on repair fidelity. J. Biol. Chem. 2001, 276:24323-24330. 10.1074/jbc.M010544200.
50. Nussenzweig A., Sokol K., Burgman P., Li L., Li G.C. Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development. Proc. Natl. Acad. Sci. U. S. A. 1997, 94:13588-13593.
51. Difilippantonio M.J., Zhu J., Chen H.T., Meffre E., Nussenzweig M.C., Max E.E., Ried T., Nussenzweig A. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 2000, 404:510-514. 10.1038/35006670.
52. Ferguson D.O., Sekiguchi J.M., Chang S., Frank K.M., Gao Y., DePinho R.A., Alt F.W. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc. Natl. Acad. Sci. U. S. A. 2000, 97:6630-6633. 10.1073/pnas.110152897.
53. Blier P.R., Griffith A.J., Craft J., Hardin J.A. Binding of Ku protein to DNA. Measurement of affinity for ends and demonstration of binding to nicks. J. Biol. Chem. 1993, 268:7594-7601.
54. Mari P.O., Florea B.I., Persengiev S.P., Verkaik N.S., Bruggenwirth H.T., Modesti M., Giglia-Mari G., Bezstarosti K., Demmers J.A., Luider T.M., Houtsmuller A.B., van Gent D.C. Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4. Proc. Natl. Acad. Sci. U. S. A. 2006, 103:18597-18602. 10.1073/pnas.0609061103.
55. Mimitou E.P., Symington L.S. Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. EMBO J. 2010, 29:3358-3369. 10.1038/emboj.2010.193.
56. Roberts S.A., Ramsden D.A. Loading of the nonhomologous end joining factor, Ku, on protein-occluded DNA ends. J. Biol. Chem. 2007, 282:10605-10613. 10.1074/jbc.M611125200.
57. Britton S., Coates J., Jackson S.P. A new method for high-resolution imaging of Ku foci to decipher mechanisms of DNA double-strand break repair. J. Cell Biol. 2013, 202:579-595. 10.1083/jcb.201303073.
58. Lovejoy C.A., Cortez D. Common mechanisms of PIKK regulation. DNA Repair (Amst.) 2009, 8:1004-1008. 10.1016/j.dnarep.2009.04.006.
59. Rivera-Calzada A., Spagnolo L., Pearl L.H., Llorca O. Structural model of full-length human Ku70-Ku80 heterodimer and its recognition of DNA and DNA-PKcs. EMBO Rep. 2007, 8:56-62. 10.1038/sj.embor.7400847.
60. Hammel M., Yu Y., Mahaney B.L., Cai B., Ye R., Phipps B.M., Rambo R.P., Hura G.L., Pelikan M., So S., Abolfath R.M., Chen D.J., Lees-Miller S.P., Tainer J.A. Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex. J. Biol. Chem. 2010, 285:1414-1423. 10.1074/jbc.M109.065615.
61. Douglas P., Sapkota G.P., Morrice N., Yu Y., Goodarzi A.A., Merkle D., Meek K., Alessi D.R., Lees-Miller S.P. Identification of in vitro and in vivo phosphorylation sites in the catalytic subunit of the DNA-dependent protein kinase. Biochem. J. 2002, 368:243-251. 10.1042/BJ20020973.
62. Chan D.W., Chen B.P., Prithivirajsingh S., Kurimasa A., Story M.D., Qin J., Chen D.J. Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev. 2002, 16:2333-2338. 10.1101/gad.1015202.
63. Yu Y., Wang W., Ding Q., Ye R., Chen D., Merkle D., Schriemer D., Meek K., Lees-Miller S.P. DNA-PK phosphorylation sites in XRCC4 are not required for survival after radiation or for V(D)J recombination. DNA Repair (Amst.) 2003, 2:1239-1252.
64. Chen B.P., Chan D.W., Kobayashi J., Burma S., Asaithamby A., Morotomi-Yano K., Botvinick E., Qin J., Chen D.J. Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double strand breaks. J. Biol. Chem. 2005, 280:14709-14715. 10.1074/jbc.M408827200.
65. Douglas P., Cui X., Block W.D., Yu Y., Gupta S., Ding Q., Ye R., Morrice N., Lees-Miller S.P., Meek K. The DNA-dependent protein kinase catalytic subunit is phosphorylated in vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain. Mol. Cell. Biol. 2007, 27:1581-1591. 10.1128/MCB. 01962-06.
66. Douglas P., Gupta S., Morrice N., Meek K., Lees-Miller S.P. DNA-PK-dependent phosphorylation of Ku70/80 is not required for non-homologous end joining. DNA Repair (Amst.) 2005, 4:1006-1018. 10.1016/j.dnarep.2005.05.003.
67. Yu Y., Mahaney B.L., Yano K., Ye R., Fang S., Douglas P., Chen D.J., Lees-Miller S.P. DNA-PK and ATM phosphorylation sites in XLF/Cernunnos are not required for repair of DNA double strand breaks. DNA Repair (Amst.) 2008, 7:1680-1692. 10.1016/j.dnarep.2008.06.015.
68. Goodarzi A.A., Yu Y., Riballo E., Douglas P., Walker S.A., Ye R., Harer C., Marchetti C., Morrice N., Jeggo P.A., Lees-Miller S.P. DNA-PK autophosphorylation facilitates Artemis endonuclease activity. EMBO J. 2006, 25:3880-3889. 10.1038/sj.emboj.7601255.
69. Wang Y.G., Nnakwe C., Lane W.S., Modesti M., Frank K.M. Phosphorylation and regulation of DNA ligase IV stability by DNA-dependent protein kinase. J. Biol. Chem. 2004, 279:37282-37290. 10.1074/jbc.M401217200.
70. Ramsden D.A., Gellert M. Ku protein stimulates DNA end joining by mammalian DNA ligases: a direct role for Ku in repair of DNA double-strand breaks. EMBO J. 1998, 17:609-614. 10.1093/emboj/17.2.609.
71. Cary R.B., Peterson S.R., Wang J., Bear D.G., Bradbury E.M., Chen D.J. DNA looping by Ku and the DNA-dependent protein kinase. Proc. Natl. Acad. Sci. U. S. A. 1997, 94:4267-4272.
72. Soutoglou E., Dorn J.F., Sengupta K., Jasin M., Nussenzweig A., Ried T., Danuser G., Misteli T. Positional stability of single double-strand breaks in mammalian cells. Nat. Cell Biol. 2007, 9:675-682. 10.1038/ncb1591.
73. Mahaney B.L., Meek K., Lees-Miller S.P. Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem. J. 2009, 417:639-650. 10.1042/BJ20080413.
74. Zeng Z., Cortes-Ledesma F., El Khamisy S.F., Caldecott K.W. TDP2/TTRAP is the major 5'-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. J. Biol. Chem. 2011, 286:403-409. 10.1074/jbc.M110.181016.
75. Gomez-Herreros F., Romero-Granados R., Zeng Z., Alvarez-Quilon A., Quintero C., Ju L., Umans L., Vermeire L., Huylebroeck D., Caldecott K.W., Cortes-Ledesma F. TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. PLoS Genet. 2013, 9:e1003226. 10.1371/journal.pgen.1003226.
76. Costantini S., Woodbine L., Andreoli L., Jeggo P.A., Vindigni A. Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK. DNA Repair (Amst.) 2007, 6:712-722. 10.1016/j.dnarep.2006.12.007.
77. Hsu H.L., Yannone S.M., Chen D.J. Defining interactions between DNA-PK and ligase IV/XRCC4. DNA Repair (Amst.) 2002, 1:225-235. 10.1016/S1568-7864(01)00018-0.
78. Yano K., Morotomi-Yano K., Wang S.Y., Uematsu N., Lee K.J., Asaithamby A., Weterings E., Chen D.J. Ku recruits XLF to DNA double-strand breaks. EMBO Rep. 2008, 9:91-96. 10.1038/sj.embor.7401137.
79. Yano K., Morotomi-Yano K., Lee K.J., Chen D.J. Functional significance of the interaction with Ku in DNA double-strand break recognition of XLF. FEBS Lett. 2011, 585:841-846. 10.1016/j.febslet.2011.02.020.
80. Reynolds P., Anderson J.A., Harper J.V., Hill M.A., Botchway S.W., Parker A.W., O'Neill P. The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage. Nucleic Acids Res. 2012, 40:10821-10831. 10.1093/nar/gks879.
81. Datta K., Jaruga P., Dizdaroglu M., Neumann R.D., Winters T.A. Molecular analysis of base damage clustering associated with a site-specific radiation-induced DNA double-strand break. Radiat. Res. 2006, 166:767-781. 10.1667/RR0628.1.
82. Datta K., Neumann R.D., Winters T.A. Characterization of complex apurinic/apyrimidinic-site clustering associated with an authentic site-specific radiation-induced DNA double-strand break. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:10569-10574. 10.1073/pnas.0503975102.
83. Datta K., Neumann R.D., Winters T.A. Characterization of a complex 125I-induced DNA double-strand break: implications for repair. Int. J. Radiat. Biol. 2005, 81:13-21.
84. Kim J.S., Krasieva T.B., Kurumizaka H., Chen D.J., Taylor A.M., Yokomori K. Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells. J. Cell Biol. 2005, 170:341-347. 10.1083/jcb.200411083.
85. Postow L., Ghenoiu C., Woo E.M., Krutchinsky A.N., Chait B.T., Funabiki H. Ku80 removal from DNA through double strand break-induced ubiquitylation. J. Cell Biol. 2008, 182:467-479. 10.1083/jcb.200802146.
86. Feng L., Chen J. The E3 ligase RNF8 regulates KU80 removal and NHEJ repair. Nat. Struct. Mol. Biol. 2012, 19:201-206. 10.1038/nsmb.2211.
87. Langerak P., Mejia-Ramirez E., Limbo O., Russell P. Release of Ku and MRN from DNA ends by Mre11 nuclease activity and Ctp1 is required for homologous recombination repair of double-strand breaks. PLoS Genet. 2011, 7:e1002271. 10.1371/journal.pgen.1002271.
88. Neale M.J., Pan J., Keeney S. Endonucleolytic processing of covalent protein-linked DNA double-strand breaks. Nature 2005, 436:1053-1057. 10.1038/nature03872.
89. Wu D., Topper L.M., Wilson T.E. Recruitment and dissociation of nonhomologous end joining proteins at a DNA double-strand break in Saccharomyces cerevisiae. Genetics 2008, 178:1237-1249. 10.1534/genetics.107.083535.
90. Pierce A.J., Hu P., Han M., Ellis N., Jasin M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 2001, 15:3237-3242. 10.1101/gad.946401.
91. Frank-Vaillant M., Marcand S. Transient stability of DNA ends allows nonhomologous end joining to precede homologous recombination. Mol. Cell 2002, 10:1189-1199. 10.1016/S1097-2765(02)00705-0.
92. Allen C., Kurimasa A., Brenneman M.A., Chen D.J., Nickoloff J.A. DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination. Proc. Natl. Acad. Sci. U. S. A. 2002, 99:3758-3763. 10.1073/pnas.052545899.
93. Clerici M., Mantiero D., Guerini I., Lucchini G., Longhese M.P. The Yku70-Yku80 complex contributes to regulate double-strand break processing and checkpoint activation during the cell cycle. EMBO Rep. 2008, 9:810-818. 10.1038/embor.2008.121.
94. Barlow J.H., Lisby M., Rothstein R. Differential regulation of the cellular response to DNA double-strand breaks in G1. Mol. Cell 2008, 30:73-85. 10.1016/j.molcel.2008.01.016.
95. Tomita K., Matsuura A., Caspari T., Carr A.M., Akamatsu Y., Iwasaki H., Mizuno K., Ohta K., Uritani M., Ushimaru T., Yoshinaga K., Ueno M. Competition between the Rad50 complex and the Ku heterodimer reveals a role for Exo1 in processing double-strand breaks but not telomeres. Mol. Cell. Biol. 2003, 23:5186-5197. 10.1128/MCB.23.15.5186-5197.2003.
96. Shim E.Y., Chung W.H., Nicolette M.L., Zhang Y., Davis M., Zhu Z., Paull T.T., Ira G., Lee S.E. Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks. EMBO J. 2010, 29:3370-3380. 10.1038/emboj.2010.219.
97. Shibata A., Conrad S., Birraux J., Geuting V., Barton O., Ismail A., Kakarougkas A., Meek K., Taucher-Scholz G., Lobrich M., Jeggo P.A. Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J. 2011, 30:1079-1092. 10.1038/emboj.2011.27.
98. Walden H., Deans A.J. The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder. Annu. Rev. Biophys. 2014, 43:257-278. 10.1146/annurev-biophys-051013-022737.
99. Pace P., Mosedale G., Hodskinson M.R., Rosado I.V., Sivasubramaniam M., Patel K.J. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science 2010, 329:219-223. 10.1126/science.1192277.
100. Carr A.M., Lambert S. Replication stress-induced genome instability: the dark side of replication maintenance by homologous recombination. J. Mol. Biol. 2013, 425:4733-4744. 10.1016/j.jmb.2013.04.023.
101. Foster S.S., Balestrini A., Petrini J.H. Functional interplay of the Mre11 nuclease and Ku in the response to replication-associated DNA damage. Mol. Cell. Biol. 2011, 31:4379-4389. 10.1128/MCB. 05854-11.
102. Balestrini A., Ristic D., Dionne I., Liu X.Z., Wyman C., Wellinger R.J., Petrini J.H. The Ku heterodimer and the metabolism of single-ended DNA double-strand breaks. Cell Rep. 2013, 3:2033-2045. 10.1016/j.celrep.2013.05.026.
103. Wang H., Perrault A.R., Takeda Y., Qin W., Wang H., Iliakis G. Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res. 2003, 31:5377-5388.
104. Betermier M., Bertrand P., Lopez B.S. Is non-homologous end-joining really an inherently error-prone process?. PLoS Genet. 2014, 10:e1004086. 10.1371/journal.pgen.1004086.
105. Guirouilh-Barbat J., Huck S., Lopez B.S. S-phase progression stimulates both the mutagenic KU-independent pathway and mutagenic processing of KU-dependent intermediates, for nonhomologous end joining. Oncogene 2008, 27:1726-1736. 10.1038/sj.onc.1210807.
106. Rothkamm K., Kruger I., Thompson L.H., Lobrich M. Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol. Cell. Biol. 2003, 23:5706-5715.
107. Wang M., Wu W., Rosidi B., Zhang L., Wang H., Iliakis G. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res. 2006, 34:6170-6182. 10.1093/nar/gkl840.
108. Mansour W.Y., Borgmann K., Petersen C., Dikomey E., Dahm-Daphi J. The absence of Ku but not defects in classical non-homologous end-joining is required to trigger PARP1-dependent end-joining. DNA Repair (Amst.) 2013, 12:1134-1142. 10.1016/j.dnarep.2013.10.005.
109. Cheng Q., Barboule N., Frit P., Gomez D., Bombarde O., Couderc B., Ren G.S., Salles B., Calsou P. Ku counteracts mobilization of PARP1 and MRN in chromatin damaged with DNA double-strand breaks. Nucleic Acids Res. 2011, 39:9605-9619. 10.1093/nar/gkr656.
110. Ariumi Y., Masutani M., Copeland T.D., Mimori T., Sugimura T., Shimotohno K., Ueda K., Hatanaka M., Noda M. Suppression of the poly(ADP-ribose) polymerase activity by DNA-dependent protein kinase in vitro. Oncogene 1999, 18:4616-4625. 10.1038/sj.onc.1202823.
111. Fattah F., Lee E.H., Weisensel N., Wang Y., Lichter N., Hendrickson E.A. Ku regulates the non-homologous end joining pathway choice of DNA double-strand break repair in human somatic cells. PLoS Genet. 2010, 6:e1000855. 10.1371/journal.pgen.1000855.
112. Enserink J.M., Kolodner R.D. An overview of Cdk1-controlled targets and processes. Cell Div. 2010, 5:11. 10.1186/1747-1028-5-11.
113. Trovesi C., Manfrini N., Falcettoni M., Longhese M.P. Regulation of the DNA damage response by cyclin-dependent kinases. J. Mol. Biol. 2013, 425:4756-4766. 10.1016/j.jmb.2013.04.013.
114. Yun M.H., Hiom K. CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 2009, 459:460-463. 10.1038/nature07955.
115. Huertas P., Jackson S.P. Human CtIP mediates cell cycle control of DNA end resection and double strand break repair. J. Biol. Chem. 2009, 284:9558-9565. 10.1074/jbc.M808906200.
116. Chen X., Niu H., Chung W.H., Zhu Z., Papusha A., Shim E.Y., Lee S.E., Sung P., Ira G. Cell cycle regulation of DNA double-strand break end resection by Cdk1-dependent Dna2 phosphorylation. Nat. Struct. Mol. Biol. 2011, 18:1015-1019. 10.1038/nsmb.2105.
117. Muller-Tidow C., Ji P., Diederichs S., Potratz J., Baumer N., Kohler G., Cauvet T., Choudary C., van der Meer T., Chan W.Y., Nieduszynski C., Colledge W.H., Carrington M., Koeffler H.P., Restle A., Wiesmuller L., Sobczak-Thepot J., Berdel W.E., Serve H. The cyclin A1-CDK2 complex regulates DNA double-strand break repair. Mol. Cell. Biol. 2004, 24:8917-8928. 10.1128/MCB.24.20.8917-8928.2004.
118. Chi Y., Welcker M., Hizli A.A., Posakony J.J., Aebersold R., Clurman B.E. Identification of CDK2 substrates in human cell lysates. Genome Biol. 2008, 9:R149. 10.1186/gb-2008-9-10-r149.
119. Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal 2010, 3. 10.1126/scisignal.2000475ra3.
120. Zhang Y., Shim E.Y., Davis M., Lee S.E. Regulation of repair choice: Cdk1 suppresses recruitment of end joining factors at DNA breaks. DNA Repair (Amst.) 2009, 8:1235-1241. 10.1016/j.dnarep.2009.07.007.
121. Bothmer A., Robbiani D.F., Feldhahn N., Gazumyan A., Nussenzweig A., Nussenzweig M.C. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J. Exp. Med. 2010, 207:855-865. 10.1084/jem.20100244.
122. Bunting S.F., Callen E., Wong N., Chen H.T., Polato F., Gunn A., Bothmer A., Feldhahn N., Fernandez-Capetillo O., Cao L., Xu X., Deng C.X., Finkel T., Nussenzweig M., Stark J.M., Nussenzweig A. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 2010, 141:243-254. 10.1016/j.cell.2010.03.012.
123. Escribano-Diaz C., Orthwein A., Fradet-Turcotte A., Xing M., Young J.T., Tkac J., Cook M.A., Rosebrock A.P., Munro M., Canny M.D., Xu D., Durocher D. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol. Cell 2013, 49:872-883. 10.1016/j.molcel.2013.01.001.
124. Wei L., Lan L., Hong Z., Yasui A., Ishioka C., Chiba N. Rapid recruitment of BRCA1 to DNA double-strand breaks is dependent on its association with Ku80. Mol. Cell. Biol. 2008, 28:7380-7393. 10.1128/MCB. 01075-08.
125. Jiang G., Plo I., Wang T., Rahman M., Cho J.H., Yang E., Lopez B.S., Xia F. BRCA1-Ku80 protein interaction enhances end-joining fidelity of chromosomal double-strand breaks in the G1 phase of the cell cycle. J. Biol. Chem. 2013, 288:8966-8976. 10.1074/jbc.M112.412650.
126. Lin W.Y., Wilson J.H., Lin Y. Repair of chromosomal double-strand breaks by precise ligation in human cells. DNA Repair (Amst.) 2013, 12:480-487. 10.1016/j.dnarep.2013.04.024.
127. Krokan H.E., Bjoras M. Base excision repair. Cold Spring Harb. Perspect. Biol. 2013, 5. 10.1101/cshperspect.a012583a012583.
128. Li H., Marple T., Hasty P. Ku80-deleted cells are defective at base excision repair. Mutat. Res. 2013, 745-746:16-25. 10.1016/j.mrfmmm.2013.03.010.
129. Choi Y.J., Li H., Son M.Y., Wang X.H., Fornsaglio J.L., Sobol R.W., Lee M., Vijg J., Imholz S., Dolle M.E., van Steeg H., Reiling E., Hasty P. Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair. PLOS ONE 2014, 9:e86358. 10.1371/journal.pone.0086358.
130. Li P., Gao S., Wang L., Yu F., Li J., Wang C., Li J., Wong J. ABH2 couples regulation of ribosomal DNA transcription with DNA alkylation repair. Cell Rep. 2013, 4:817-829. 10.1016/j.celrep.2013.07.027.
131. Giglia-Mari G., Zotter A., Vermeulen W. DNA damage response. Cold Spring Harb. Perspect. Biol. 2011, 3. a000745. 10.1101/cshperspect.a000745.
132. Marechal A., Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol. 2013, 5. 10.1101/cshperspect.a012716.
133. Shiloh Y., Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more, Nature reviews. Mol. Cell Biol. 2013, 14:197-210.
134. Nam E.A., Cortez D. ATR signalling: more than meeting at the fork. Biochem. J. 2011, 436:527-536. 10.1042/BJ20102162.
135. Tomimatsu N., Tahimic C.G., Otsuki A., Burma S., Fukuhara A., Sato K., Shiota G., Oshimura M., Chen D.J., Kurimasa A. Ku70/80 modulates ATM and ATR signaling pathways in response to DNA double strand breaks. J. Biol. Chem. 2007, 282:10138-10145. 10.1074/jbc.M611880200.
136. Zhou X.Y., Wang X., Wang H., Chen D.J., Li G.C., Iliakis G., Wang Y. Ku affects the ATM-dependent S phase checkpoint following ionizing radiation. Oncogene 2002, 21:6377-6381. 10.1038/sj.onc.1205782.
137. Stracker T.H., Petrini J.H. The MRE11 complex: starting from the ends. Nat. Rev. Mol. Cell Biol. 2011, 12:90-103. 10.1038/nrm3047.
138. Amsel A.D., Rathaus M., Kronman N., Cohen H.Y. Regulation of the proapoptotic factor Bax by Ku70-dependent deubiquitylation. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:5117-5122. 10.1073/pnas.0706700105.
139. Sawada M., Sun W., Hayes P., Leskov K., Boothman D.A., Matsuyama S. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat. Cell Biol. 2003, 5:320-329. 10.1038/ncb950.
140. Iijima K., Muranaka C., Kobayashi J., Sakamoto S., Komatsu K., Matsuura S., Kubota N., Tauchi H. NBS1 regulates a novel apoptotic pathway through Bax activation. DNA Repair (Amst.) 2008, 7:1705-1716. 10.1016/j.dnarep.2008.06.013.
141. Mazumder S., Plesca D., Kinter M., Almasan A. Interaction of a cyclin E fragment with Ku70 regulates Bax-mediated apoptosis. Mol. Cell. Biol. 2007, 27:3511-3520. 10.1128/MCB. 01448-06.
142. Subramanian C., Jarzembowski J.A., Opipari A.W., Castle V.P., Kwok R.P. HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma. Neoplasia 2011, 13:726-734.
143. Yuan Z., Seto E. A functional link between SIRT1 deacetylase and NBS1 in DNA damage response. Cell Cycle 2007, 6:2869-2871. 10.4161/cc.6.23.5026.
144. Wang B., Xie M., Li R., Owonikoko T.K., Ramalingam S.S., Khuri F.R., Curran W.J., Wang Y., Deng X. Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis. Cell Death Differ. 2014, 10.1038/cdd.2014.42.
145. Martinou J.C., Youle R.J. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev. Cell 2011, 21:92-101. 10.1016/j.devcel.2011.06.017.
146. Longhese M.P., Anbalagan S., Martina M., Bonetti D. The role of shelterin in maintaining telomere integrity. Front. Biosci. 2012, 17:1715-1728.
147. Price C.M., Boltz K.A., Chaiken M.F., Stewart J.A., Beilstein M.A., Shippen D.E. Evolution of CST function in telomere maintenance. Cell Cycle 2010, 9:3157-3165. 10.4161/cc.9.16.12547.
148. Porter S.E., Greenwell P.W., Ritchie K.B., Petes T.D. The DNA-binding protein Hdf1p (a putative Ku homologue) is required for maintaining normal telomere length in Saccharomyces cerevisiae. Nucleic Acids Res. 1996, 24:582-585. 10.1093/nar/24.4.582.
149. Boulton S.J., Jackson S.P. Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double strand break rejoining and in telomeric maintenance. Nucleic Acids Res. 1996, 24:4639-4648. 10.1093/nar/24.23.4639.
150. Gravel S., Larrivee M., Labrecque P., Wellinger R.J., Yeast Ku as a regulator of chromosomal DNA end structure. Science 1998, 280:741-744. 10.1126/science.280.5364.741.
151. Teo S.H., Jackson S.P. Identification of Saccharomyces cerevisiae DNA ligase IV: involvement in DNA double-strand break repair. EMBO J. 1997, 16:4788-4795. 10.1093/emboj/16.15.4788.
152. d'Adda di Fagagna F., Hande M.P., Tong W.M., Roth D., Lansdorp P.M., Wang Z.Q., Jackson S.P. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr. Biol. 2001, 11:1192-1196. 10.1016/S0960-9822(01)00328-1.
153. Samper E., Goytisolo F.A., Slijepcevic P., van Buul P.P., Blasco M.A. Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep. 2000, 1:244-252. 10.1093/embo-reports/kvd051.
154. Espejel S., Franco S., Rodriguez-Perales S., Bouffler S.D., Cigudosa J.C., Blasco M.A. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J. 2002, 21:2207-2219. 10.1093/emboj/21.9.2207.
155. Wang Y., Ghosh G., Hendrickson E.A. Ku86 represses lethal telomere deletion events in human somatic cells. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:12430-12435. 10.1073/pnas.0903362106.
156. Celli G.B., Denchi E.L., de Lange T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat. Cell Biol. 2006, 8:885-890. 10.1038/ncb1444.
157. Sfeir A., de Lange T. Removal of shelterin reveals the telomere end-protection problem. Science 2012, 336:593-597. 10.1126/science.1218498.
158. Fellerhoff B., Eckardt-Schupp F., Friedl A.A. Subtelomeric repeat amplification is associated with growth at elevated temperature in yku70 mutants of Saccharomyces cerevisiae. Genetics 2000, 154:1039-1051.
159. Lundblad V., Blackburn E.H. An alternative pathway for yeast telomere maintenance rescues est1-senescence. Cell 1993, 73:347-360. pii:0092-8674(93)90234-H.
160. Maringele L., Lydall D. EXO1-dependent single-stranded DNA at telomeres activates subsets of DNA damage and spindle checkpoint pathways in budding yeast yku70Delta mutants. Genes Dev. 2002, 16:1919-1933. 10.1101/gad.225102.
161. Stellwagen A.E., Haimberger Z.W., Veatch J.R., Gottschling D.E. Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev. 2003, 17:2384-2395. 10.1101/gad.1125903.
162. Fisher T.S., Taggart A.K., Zakian V.A. Cell cycle-dependent regulation of yeast telomerase by Ku. Nat. Struct. Mol. Biol. 2004, 11:1198-1205. 10.1038/nsmb854.
163. Peterson S.E., Stellwagen A.E., Diede S.J., Singer M.S., Haimberger Z.W., Johnson C.O., Tzoneva M., Gottschling D.E. The function of a stem-loop in telomerase RNA is linked to the DNA repair protein Ku. Nat. Genet. 2001, 27:64-67. 10.1038/83778.
164. Mozdy A.D., Podell E.R., Cech T.R. Multiple yeast genes, including Paf1 complex genes, affect telomere length via telomerase RNA abundance. Mol. Cell. Biol. 2008, 28:4152-4161. 10.1128/MCB. 00512-08.
165. Zappulla D.C., Goodrich K.J., Arthur J.R., Gurski L.A., Denham E.M., Stellwagen A.E., Cech T.R. Ku can contribute to telomere lengthening in yeast at multiple positions in the telomerase RNP. RNA 2011, 17:298-311. 10.1261/rna.2483611.
166. Gallardo F., Olivier C., Dandjinou A.T., Wellinger R.J., Chartrand P. TLC1 RNA nucleo-cytoplasmic trafficking links telomerase biogenesis to its recruitment to telomeres. EMBO J. 2008, 27:748-757. 10.1038/emboj.2008.21.
167. Ting N.S., Yu Y., Pohorelic B., Lees-Miller S.P., Beattie T.L. Human Ku70/80 interacts directly with hTR, the RNA component of human telomerase. Nucleic Acids Res. 2005, 33:2090-2098. 10.1093/nar/gki342.
168. Chai W., Ford L.P., Lenertz L., Wright W.E., Shay J.W. Human Ku70/80 associates physically with telomerase through interaction with hTERT. J. Biol. Chem. 2002, 277:47242-47247. 10.1074/jbc.M208542200.
169. Mekhail K., Moazed D. The nuclear envelope in genome organization, expression and stability. Nat. Rev. Mol. Cell Biol. 2010, 11:317-328. 10.1038/nrm2894.
170. Kueng S., Oppikofer M., Gasser S.M. SIR proteins and the assembly of silent chromatin in budding yeast. Annu. Rev. Genet. 2013, 47:275-306. 10.1146/annurev-genet-021313-173730.
171. Aparicio O.M., Billington B.L., Gottschling D.E. Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell 1991, 66:1279-1287.
172. Boulton S.J., Jackson S.P. Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO J. 1998, 17:1819-1828. 10.1093/emboj/17.6.1819.
173. Nugent C.I., Bosco G., Ross L.O., Evans S.K., Salinger A.P., Moore J.K., Haber J.E., Lundblad V. Telomere maintenance is dependent on activities required for end repair of double-strand breaks. Curr. Biol. 1998, 8:657-660.
174. Laroche T., Martin S.G., Gotta M., Gorham H.C., Pryde F.E., Louis E.J., Gasser S.M. Mutation of yeast Ku genes disrupts the subnuclear organization of telomeres. Curr. Biol. 1998, 8:653-656.
175. Gotta M., Laroche T., Formenton A., Maillet L., Scherthan H., Gasser S.M. The clustering of telomeres and colocalization with Rap1, Sir3, and Sir4 proteins in wild-type Saccharomyces cerevisiae. J. Cell Biol. 1996, 134:1349-1363.
176. Taddei A., Hediger F., Neumann F.R., Bauer C., Gasser S.M. Separation of silencing from perinuclear anchoring functions in yeast Ku80, Sir4 and Esc1 proteins. EMBO J. 2004, 23:1301-1312. 10.1038/sj.emboj.7600144.
177. Schober H., Ferreira H., Kalck V., Gehlen L.R., Gasser S.M. Yeast telomerase and the SUN domain protein Mps3 anchor telomeres and repress subtelomeric recombination. Genes Dev. 2009, 23:928-938. 10.1101/gad.1787509.
178. Hediger F., Neumann F.R., Van Houwe G., Dubrana K., Gasser S.M. Live imaging of telomeres: yKu and Sir proteins define redundant telomere-anchoring pathways in yeast. Curr. Biol. 2002, 12:2076-2089.
179. Hsu H.L., Gilley D., Blackburn E.H., Chen D.J. Ku is associated with the telomere in mammals. Proc. Natl. Acad. Sci. U. S. A. 1999, 96:12454-12458. 10.1073/pnas.96.22.12454.
180. Wu T.J., Chiang Y.H., Lin Y.C., Tsai C.R., Yu T.Y., Sung M.T., Lee Y.H., Lin J.J. Sequential loading of Saccharomyces cerevisiae Ku and Cdc13p to telomeres. J. Biol. Chem. 2009, 284:12801-12808. 10.1074/jbc.M809131200.
181. Lopez C.R., Ribes-Zamora A., Indiviglio S.M., Williams C.L., Haricharan S., Bertuch A.A. Ku must load directly onto the chromosome end in order to mediate its telomeric functions. PLoS Genet. 2011, 7:e1002233. 10.1371/journal.pgen.1002233.
182. Bianchi A., de Lange T. Ku binds telomeric DNA in vitro. J. Biol. Chem. 1999, 274:21223-21227.
183. Hsu H.L., Gilley D., Galande S.A., Hande M.P., Allen B., Kim S.H., Li G.C., Campisi J., Kohwi-Shigematsu T., Chen D.J. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev. 2000, 14:2807-2812. 10.1101/gad.844000.
184. Song K., Jung D., Jung Y., Lee S.G., Lee I. Interaction of human Ku70 with TRF2. FEBS Lett. 2000, 481:81-85. 10.1016/S0014-5793(00)01958-X.
185. Fink L.S., Lerner C.A., Torres P.F., Sell C. Ku80 facilitates chromatin binding of the telomere binding protein, TRF2. Cell Cycle 2010, 9:3798-3806. 10.4161/cc.9.18.13129.
186. O'Connor M.S., Safari A., Liu D., Qin J., Songyang Z. The human Rap1 protein complex and modulation of telomere length. J. Biol. Chem. 2004, 279:28585-28591. 10.1074/jbc.M312913200.
187. Ye J.Z., Donigian J.R., van Overbeek M., Loayza D., Luo Y., Krutchinsky A.N., Chait B.T., de Lange T. TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J. Biol. Chem. 2004, 279:47264-47271. 10.1074/jbc.M409047200.
188. Cockell M., Palladino F., Laroche T., Kyrion G., Liu C., Lustig A.J., Gasser S.M. The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing. J. Cell Biol. 1995, 129:909-924.
189. Pfingsten J.S., Goodrich K.J., Taabazuing C., Ouenzar F., Chartrand P., Cech T.R. Mutually exclusive binding of telomerase RNA and DNA by Ku alters telomerase recruitment model. Cell 2012, 148:922-932. 10.1016/j.cell.2012.01.033.
190. Lei M., Podell E.R., Cech T.R. Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat. Struct. Mol. Biol. 2004, 11:1223-1229. 10.1038/nsmb867.
191. Liu D., Safari A., O'Connor M.S., Chan D.W., Laegeler A., Qin J., Songyang Z. PTOP interacts with POT1 and regulates its localization to telomeres. Nat. Cell Biol. 2004, 6:673-680. 10.1038/ncb1142.
192. Doksani Y., Wu J.Y., de Lange T., Zhuang X. Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell 2013, 155:345-356. 10.1016/j.cell.2013.09.048.
193. Malu S., Malshetty V., Francis D., Cortes P. Role of non-homologous end joining in V(D)J recombination. Immunol. Res. 2012, 54:233-246. 10.1007/s12026-012-8329-z.
194. Ouyang H., Nussenzweig A., Kurimasa A., Soares V.C., Li X., Cordon-Cardo C., Li W., Cheong N., Nussenzweig M., Iliakis G., Chen D.J., Li G.C. Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J. Exp. Med. 1997, 186:921-929. 10.1084/jem.186.6.921.
195. Manis J.P., Gu Y., Lansford R., Sonoda E., Ferrini R., Davidson L., Rajewsky K., Alt F.W. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J. Exp. Med. 1998, 187:2081-2089. 10.1084/jem.187.12.2081.
196. Gu Y., Seidl K.J., Rathbun G.A., Zhu C., Manis J.P., van der Stoep N., Davidson L., Cheng H.L., Sekiguchi J.M., Frank K., Stanhope-Baker P., Schlissel M.S., Roth D.B., Alt F.W. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 1997, 7:653-665. 10.1016/S1074-7613(00)80386-6.
197. Slatter M.A., Gennery A.R. Primary immunodeficiency syndromes. Adv. Exp. Med. Biol. 2010, 685:146-165.
198. Moshous D., Callebaut I., de Chasseval R., Corneo B., Cavazzana-Calvo M., Le Deist F., Tezcan I., Sanal O., Bertrand Y., Philippe N., Fischer A., de Villartay J.P. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 2001, 105:177-186. 10.1016/S0092-8674(01)00309-9.
199. O'Driscoll M., Cerosaletti K.M., Girard P.M., Dai Y., Stumm M., Kysela B., Hirsch B., Gennery A., Palmer S.E., Seidel J., Gatti R.A., Varon R., Oettinger M.A., Neitzel H., Jeggo P.A., Concannon P. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol. Cell 2001, 8:1175-1185. 10.1016/S1097-2765(01)00408-7.
200. Buck D., Malivert L., de Chasseval R., Barraud A., Fondaneche M.C., Sanal O., Plebani A., Stephan J.L., Hufnagel M., le Deist F., Fischer A., Durandy A., de Villartay J.P., Revy P., Cernunnos a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 2006, 124:287-299. 10.1016/j.cell.2005.12.030.
201. Woodbine L., Neal J.A., Sasi N.K., Shimada M., Deem K., Coleman H., Dobyns W.B., Ogi T., Meek K., Davies E.G., Jeggo P.A. PRKDC mutations in a SCID patient with profound neurological abnormalities. J. Clin. Invest. 2013, 123:2969-2980. 10.1172/JCI67349.
202. van der Burg M., van Dongen J.J., van Gent D.C. DNA-PKcs deficiency in human: long predicted, finally found. Curr. Opin. Allergy Clin. Immunol. 2009, 9:503-509. 10.1097/ACI.0b013e3283327e41.
203. Li G.C., Ouyang H., Li X., Nagasawa H., Little J.B., Chen D.J., Ling C.C., Fuks Z., Cordon-Cardo C. Ku70: a candidate tumor suppressor gene for murine T cell lymphoma. Mol. Cell 1998, 2:1-8. 10.1016/S1097-2765(00)80108-2.
204. Vogel H., Lim D.S., Karsenty G., Finegold M., Hasty P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl. Acad. Sci. U. S. A. 1999, 96:10770-10775. 10.1073/pnas.96.19.10770.
205. Nussenzweig A., Chen C., da Costa Soares V., Sanchez M., Sokol K., Nussenzweig M.C., Li G.C. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 1996, 382:551-555. 10.1038/382551a0.
206. Li H., Vogel H., Holcomb V.B., Gu Y., Hasty P. Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer. Mol. Cell. Biol. 2007, 27:8205-8214. 10.1128/MCB. 00785-07.
207. Ren K., Pena de Ortiz S. Non-homologous DNA end joining in the mature rat brain. J. Neurochem. 2002, 80:949-959. 10.1046/j.0022-3042.2002.00776.x.
208. Vyjayanti V.N., Rao K.S. DNA double strand break repair in brain: reduced NHEJ activity in aging rat neurons. Neurosci. Lett. 2006, 393:18-22. 10.1016/j.neulet.2005.09.053.
209. Shackelford D.A. DNA end joining activity is reduced in Alzheimer's disease. Neurobiol. Aging 2006, 27:596-605. 10.1016/j.neurobiolaging.2005.03.009.
210. Reaper P.M., di Fagagna F., Jackson S.P. Activation of the DNA damage response by telomere attrition: a passage to cellular senescence. Cell Cycle 2004, 3:543-546. 10.4161/cc.3.5.835.
211. Shammas M.A. Telomeres, lifestyle, cancer, and aging. Curr. Opin. Clin. Nutr. Metab. Care 2011, 14:28-34. 10.1097/MCO.0b013e32834121b1.
212. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011, 144:646-674. 10.1016/j.cell.2011.02.013.
213. Luk J.M., Su Y.C., Lam S.C., Lee C.K., Hu M.Y., He Q.Y., Lau G.K., Wong F.W., Fan S.T. Proteomic identification of Ku70/Ku80 autoantigen recognized by monoclonal antibody against hepatocellular carcinoma. Proteomics 2005, 5:1980-1986. 10.1002/pmic.200401084.
214. Korabiowska M., Voltmann J., Honig J.F., Bortkiewicz P., Konig F., Cordon-Cardo C., Jenckel F., Ambrosch P., Fischer G. Altered expression of DNA double-strand repair genes Ku70 and Ku80 in carcinomas of the oral cavity. Anticancer Res. 2006, 26:2101-2105.
215. Mazzarelli P., Parrella P., Seripa D., Signori E., Perrone G., Rabitti C., Borzomati D., Gabbrielli A., Matera M.G., Gravina C., Caricato M., Poeta M.L., Rinaldi M., Valeri S., Coppola R., Fazio V.M. DNA end binding activity and Ku70/80 heterodimer expression in human colorectal tumor. World J. Gastroenterol.: WJG 2005, 11:6694-6700.
216. Parrella P., Mazzarelli P., Signori E., Perrone G., Marangi G.F., Rabitti C., Delfino M., Prencipe M., Gallo A.P., Rinaldi M., Fabbrocini G., Delfino S., Persichetti P., Fazio V.M. Expression and heterodimer-binding activity of Ku70 and Ku80 in human non-melanoma skin cancer. J. Clin. Pathol. 2006, 59:1181-1185. 10.1136/jcp.2005.031088.
217. Abdelbaqi K., Di Paola D., Rampakakis E., Zannis-Hadjopoulos M. Ku protein levels, localization and association to replication origins in different stages of breast tumor progression. J. Cancer 2013, 4:358-370. 10.7150/jca.6289.
218. Komuro Y., Watanabe T., Hosoi Y., Matsumoto Y., Nakagawa K., Tsuno N., Kazama S., Kitayama J., Suzuki N., Nagawa H. The expression pattern of Ku correlates with tumor radiosensitivity and disease free survival in patients with rectal carcinoma. Cancer 2002, 95:1199-1205. 10.1002/cncr.10807.
219. Lord C.J., Ashworth A. The DNA damage response and cancer therapy. Nature 2012, 481:287-294. 10.1038/nature10760.
220. Kim C.H., Park S.J., Lee S.H. A targeted inhibition of DNA-dependent protein kinase sensitizes breast cancer cells following ionizing radiation. J. Pharmacol. Exp. Ther. 2002, 303:753-759. 10.1124/jpet.102.038505.
221. Bertolini L.R., Bertolini M., Anderson G.B., Maga E.A., Madden K.R., Murray J.D. Transient depletion of Ku70 and Xrcc4 by RNAi as a means to manipulate the non-homologous end-joining pathway. J. Biotechnol. 2007, 128:246-257. 10.1016/j.jbiotec.2006.10.003.
222. Ayene I.S., Ford L.P., Koch C.J. Ku protein targeting by Ku70 small interfering RNA enhances human cancer cell response to topoisomerase II inhibitor and gamma radiation. Mol Cancer Ther 2005, 4:529-536. 10.1158/1535-7163.MCT-04-0130.
223. Zhu P., Zhang D., Chowdhury D., Martinvalet D., Keefe D., Shi L., Lieberman J. Granzyme A, which causes single-stranded DNA damage, targets the double-strand break repair protein Ku70. EMBO Rep. 2006, 7:431-437. 10.1038/sj.embor.7400622.
224. Yoshida T., Tomioka I., Nagahara T., Holyst T., Sawada M., Hayes P., Gama V., Okuno M., Chen Y., Abe Y., Kanouchi T., Sasada H., Wang D., Yokota T., Sato E., Matsuyama S. Bax-inhibiting peptide derived from mouse and rat Ku70. Biochem. Biophys. Res. Commun. 2004, 321:961-966. 10.1016/j.bbrc.2004.07.054.
225. Sawada M., Hayes P., Matsuyama S. Cytoprotective membrane-permeable peptides designed from the Bax-binding domain of Ku70. Nat. Cell Biol. 2003, 5:352-357. 10.1038/ncb955.
226. Subramanian C., Opipari A.W., Bian X., Castle V.P., Kwok R.P. Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:4842-4847. 10.1073/pnas.0408351102.
227. Hsu F.M., Zhang S., Chen B.P. Role of DNA-dependent protein kinase catalytic subunit in cancer development and treatment. Transl. Cancer Res. 2012, 1:22-34. 10.3978/j.issn.2218-676X.0104.
228. West R.B., Yaneva M., Lieber M.R. Productive and nonproductive complexes of Ku and DNA-dependent protein kinase at DNA termini. Mol. Cell. Biol. 1998, 18:5908-5920.
229. Mahajan K.N., Nick McElhinny S.A., Mitchell B.S., Ramsden D.A. Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair. Mol. Cell. Biol. 2002, 22:5194-5202. 10.1128/MCB.22.14.5194-5202.2002.
230. Ma Y., Lu H., Tippin B., Goodman M.F., Shimazaki N., Koiwai O., Hsieh C.L., Schwarz K., Lieber M.R. A biochemically defined system for mammalian nonhomologous DNA end joining. Mol. Cell 2004, 16:701-713. 10.1016/j.molcel.2004.11.017.
231. Purugganan M.M., Shah S., Kearney J.F., Roth D.B. Ku80 is required for addition of N nucleotides to V(D)J recombination junctions by terminal deoxynucleotidyl transferase. Nucleic Acids Res. 2001, 29:1638-1646. 10.1093/nar/29.7.1638.
232. Karmakar P., Snowden C.M., Ramsden D.A., Bohr V.A. Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus. Nucleic Acids Res. 2002, 30:3583-3591.
233. Raval P., Kriatchko A.N., Kumar S., Swanson P.C. Evidence for Ku70/Ku80 association with full-length RAG1. Nucleic Acids Res. 2008, 36:2060-2072. 10.1093/nar/gkn049.
234. Kinner A., Wu W., Staudt C., Iliakis G. Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res. 2008, 36:5678-5694. 10.1093/nar/gkn550.
235. Hoek M., Myers M.P., Stillman B. An analysis of CAF-1-interacting proteins reveals dynamic and direct interactions with the KU complex and 14-3-3 proteins. J. Biol. Chem. 2011, 286:10876-10887. 10.1074/jbc.M110.217075.
236. Morales J.C., Richard P., Rommel A., Fattah F.J., Motea E.A., Patidar P.L., Xiao L., Leskov K., Wu S.Y., Hittelman W.N., Chiang C.M., Manley J.L., Boothman D.A. Kub5-Hera, the human Rtt103 homolog, plays dual functional roles in transcription termination and DNA repair. Nucleic Acids Res. 2014, 10.1093/nar/gku160.
237. Galande S., Kohwi-Shigematsu T. Poly(ADP-ribose) polymerase and Ku autoantigen form a complex and synergistically bind to matrix attachment sequences. J. Biol. Chem. 1999, 274:20521-20528.
238. Shahi A., Lee J.H., Kang Y., Lee S.H., Hyun J.W., Chang I.Y., Jun J.Y., You H.J. Mismatch-repair protein MSH6 is associated with Ku70 and regulates DNA double-strand break repair. Nucleic Acids Res. 2011, 39:2130-2143. 10.1093/nar/gkq1095.
239. Parvathaneni S., Stortchevoi A., Sommers J.A., Brosh R.M., Sharma S. Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks. PLOS ONE 2013, 8:e62481. 10.1371/journal.pone.0062481.
240. Goedecke W., Eijpe M., Offenberg H.H., van Aalderen M., Heyting C. Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis. Nat. Genet. 1999, 23:194-198. 10.1038/13821.
241. Feki A., Jefford C.E., Berardi P., Wu J.Y., Cartier L., Krause K.H., Irminger-Finger I. BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. Oncogene 2005, 24:3726-3736. 10.1038/sj.onc.1208491.
242. Song K., Jung Y., Jung D., Lee I. Human Ku70 interacts with heterochromatin protein 1alpha. J. Biol. Chem. 2001, 276:8321-8327. 10.1074/jbc.M008779200.
243. Leskov K.S., Klokov D.Y., Li J., Kinsella T.J., Boothman D.A. Synthesis and functional analyses of nuclear clusterin, a cell death protein. J. Biol. Chem. 2003, 278:11590-11600. 10.1074/jbc.M209233200.
244. Liu H., Herrmann C.H., Chiang K., Sung T.L., Moon S.H., Donehower L.A., Rice A.P. 55K isoform of CDK9 associates with Ku70 and is involved in DNA repair. Biochem. Biophys. Res. Commun. 2010, 397:245-250. 10.1016/j.bbrc.2010.05.092.
245. Chung U., Igarashi T., Nishishita T., Iwanari H., Iwamatsu A., Suwa A., Mimori T., Hata K., Ebisu S., Ogata E., Fujita T., Okazaki T. The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium. J. Biol. Chem. 1996, 271:8593-8598.
246. Zheng Y., Ao Z., Wang B., Jayappa K.D., Yao X. Host protein Ku70 binds and protects HIV-1 integrase from proteasomal degradation and is required for HIV replication. J. Biol. Chem. 2011, 286:17722-17735. 10.1074/jbc.M110.184739.
247. Wang H., Fang R., Cho J.Y., Libermann T.A., Oettgen P. Positive and negative modulation of the transcriptional activity of the ETS factor ESE-1 through interaction with p300, CREB-binding protein, and Ku 70/86. J. Biol. Chem. 2004, 279:25241-25250. 10.1074/jbc.M401356200.
248. Kaczmarski W., Khan S.A. Lupus autoantigen Ku protein binds HIV-1 TAR RNA in vitro. Biochem. Biophys. Res. Commun. 1993, 196:935-942. 10.1006/bbrc.1993.2339.
249. Willis D.M., Loewy A.P., Charlton-Kachigian N., Shao J.S., Ornitz D.M., Towler D.A. Regulation of osteocalcin gene expression by a novel Ku antigen transcription factor complex. J. Biol. Chem. 2002, 277:37280-37291. 10.1074/jbc.M206482200.
250. Huang J., Nueda A., Yoo S., Dynan W.S. Heat shock transcription factor 1 binds selectively in vitro to Ku protein and the catalytic subunit of the DNA-dependent protein kinase. J. Biol. Chem. 1997, 272:26009-26016.
251. Matheos D., Ruiz M.T., Price G.B., Zannis-Hadjopoulos M. Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication. Biochim. Biophys. Acta 2002, 1578:59-72. 10.1016/S0167-4781(02)00497-9.
252. Wellinger R.J., Zakian V.A. Everything you ever wanted to know about Saccharomyces cerevisiae telomeres: beginning to end. Genetics 2012, 191:1073-1105. 10.1534/genetics.111.137851.
253. O'Sullivan R.J., Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat. Rev. Mol. Cell Biol. 2010, 11:171-181. 10.1038/nrm2848.