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  • [1]J.H.J. Hoeijmakers, DNA damage, aging, and cancer. N Engl J Med 361, 1475–1485 (2009)

  • [2]W.P. Vermeij, J.H.J. Hoeijmakers, J. Pothof, Aging: not all DNA damage is equal. Curr Opin Genet Dev 26, 124–130 (2014)

  • [3]K. Rothkamm, M. Löbrich, Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci U S A 100, 5057–5062 (2003)

  • [4]T. Helleday, J. Lo, D.C. van Gent, B.P. Engelward, DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair (Amst.) 6, 923–935 (2007)

  • [5]D.C. van Gent, J.H. Hoeijmakers, R. Kanaar, Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2, 196–206 (2001)

  • [6]S.J. Boulton, S.P. Jackson, Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. Embo J 17, 1819–1828 (1998)

  • [7]F. d’Adda Di Fagagna, M.P. Hande, W.M. Tong, D. Roth, P.M. Lansdorp, Z.Q. Wang, S.P. Jackson, Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr Biol 11, 1192–1196 (2001)

  • [8]J. Harrington, C.L. Hsieh, J. Gerton, G. Bosma, M.R. Lieber, Analysis of the defect in DNA end joining in the murine scid mutation. Mol Cell Biol 12, 4758–4768 (1992)

  • [9]P.J. McKinnon, Maintaining genome stability in the nervous system. Nat Neurosci 16, 1523–1529 (2013)

  • [10]T. Tamura, M. Sone, T. Iwatsubo, K. Tagawa, E.E. Wanker, H. Okazawa, Ku70 alleviates neurodegeneration in Drosophila models of Huntington’s disease. PLoS One 6, e27408 (2011)

  • [11]Y. Enokido, T. Tamura, H. Ito, A. Arumughan, A. Komuro, H. Shiwaku, M. Sone, R. Foulle, H. Sawada, H. Ishiguro, T. Ono, M. Murata, I. Kanazawa, N. Tomilin, K. Tagawa, E.E. Wanker, H. Okazawa, Mutant huntingtin impairs Ku70-mediated DNA repair. J Cell Biol 189, 425–443 (2010)

  • [12]S. Bergink, S. Jentsch, Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458, 461–467 (2009)

  • [13]S.P. Jackson, D. Durocher, Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell 49, 795–807 (2013)

  • [14]S.E. Polo, S.P. Jackson, Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev 25, 409–433 (2011)

  • [15]G.J. Grundy, H.A. Moulding, K.W. Caldecott, S.L. Rulten, One ring to bring them all--the role of Ku in mammalian non-homologous end joining. DNA Repair (Amst.) 17, 30–38 (2014)

  • [16]T.S. Krishna, X.P. Kong, S. Gary, P.M. Burgers, J. Kuriyan, Crystal structure of the eukaryotic DNA polymerase processivity factor PCNA. Cell 79, 1233–1243 (1994)

  • [17]J.R. Walker, R.A. Corpina, J. Goldberg, Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607–614 (2001)

  • [18]A. Bacquin, C. Pouvelle, N. Siaud, M. Perderiset, S. Salomé-Desnoulez, C. Tellier-Lebegue, B. Lopez, J.B. Charbonnier P.L. Kannouche, The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells. Nucleic Acids Res 41, 6501–6513 (2013)

  • [19]S. Zhang, J. Chea, X. Meng, Y. Zhou, E.Y.C. Lee, M.Y.W.T. Lee, PCNA is ubiquitinated by RNF8. Cell Cycle 7, 3399–3404 (2008)

  • [20]S.K. Radhakrishnan, N. Jette, S.P. Lees-Miller, Non-homologous end joining: emerging themes and unanswered questions. DNA Repair (Amst.) 17, 2–8 (2014)

  • [21]M.P. Cooper, A. Machwe, D.K. Orren, R.M. Brosh, D. Ramsden, V.A. Bohr, Ku complex interacts with and stimulates the Werner protein. Genes Dev 14, 907–912 (2000)

  • [22]D.K. Orren, A. Machwe, P. Karmakar, J. Piotrowski, M.P. Cooper, V.A. Bohr, A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA. Nucleic Acids Res 29, 1926–1934 (2001)

  • [23]S.A. Nick McElhinny, J.M. Havener, M. Garcia-Diaz, R. Juárez, K. Bebenek, B.L. Kee, L. Blanco, T.A. Kunkel, D.A. Ramsden, A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. Mol Cell 19, 357–366 (2005)

  • [24]A.E. Zolner, I. Abdou, R. Ye, R.S. Mani, M. Fanta, Y. Yu, P. Douglas, N. Tahbaz, S. Fang, T. Dobbs, C. Wang, N. Morrice, M.J. Hendzel, M. Weinfeld, S.P. Lees-Miller, Phosphorylation of polynucleotide kinase/phosphatase by DNA-dependent protein kinase and ataxia-telangiectasia mutated regulates its association with sites of DNA damage. Nucleic Acids Res 39, 9224–9237 (2011)

  • [25]P.M. Clements, C. Breslin, E.D. Deeks, P.J. Byrd, L. Ju, P. Bieganowski, C. Brenner, M.C. Moreira, A.M. Taylor, K.W. Caldecott, The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. DNA Repair (Amst.) 3, 1493–1502 (2004)

  • [26]C.J. Macrae, R.D. McCulloch, J. Ylanko, D. Durocher, C.A. Koch, APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation. DNA Repair (Amst.) 7, 292–302 (2008)

  • [27]T. Ochi, A.N. Blackford, J. Coates, S. Jhujh, S. Mehmood, N. Tamura, J. Travers, Q. Wu, V.M. Draviam, C.V. Robinson, T.L. Blundell, S.P. Jackson, DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347, 185–188 (2015)

  • [28]P. Ahnesorg, P. Smith, S.P. Jackson, XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124, 301–313 (2006)

  • [29]D. Moshous, I. Callebaut, R. de Chasseval, B. Corneo, M. Cavazzana-Calvo, F. Le Deist, I. Tezcan, O. Sanal, Y. Bertrand, N. Philippe, A. Fisher, J.P. de Villartay, Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105, 177–186 (2001)

  • [30]M.T. Shaw, J.M. Dwyer, H.S. Allaudeen, H.A. Weitzman, Terminal deoxyribonucleotidyl transferase activity in B-cell acute lymphocytic leukemia. Blood 51, 181–187 (1978)

  • [31]E. Weterings, N.S. Verkaik, H.T. Brüggenwirth, J.H.J. Hoeijmakers, D.C. van Gent, The role of DNA dependent protein kinase in synapsis of DNA ends. Nucleic Acids Res 31, 7238–7246 (2003)

  • [32]L.G. DeFazio, R.M. Stansel, J.D. Griffith, G. Chu, Synapsis of DNA ends by DNA-dependent protein kinase. Embo J 21, 3192–3200 (2002)

  • [33]L. Spagnolo, A. Rivera-Calzada, L.H. Pearl, O. Llorca, Three-dimensional structure of the human DNA-PKcs/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair. Mol Cell 22, 511–519 (2006)

  • [34]D.W. Chan, R. Ye, C.J. Veillette, S.P. Lees-Miller, DNA-dependent protein kinase phosphorylation sites in Ku 70/80 heterodimer. Biochemistry 38, 1819–1828 (1999)

  • [35]T.A. Dobbs, J.A. Tainer, S.P. Lees-Miller, A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation. DNA Repair (Amst.) 9, 1307–1314 (2010)

  • [36]G.J. Williams, M. Hammel, S.K. Radhakrishnan, D. Ramsden, S.P. Lees-Miller, J.A. Tainer, 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.) 17, 110–120 (2014)

  • [37]Q. Ding, Y.V.R. Reddy, W. Wang, T. Woods, P. Douglas, D.A. Ramsden, S.P. Lees-Miller, K. Meek, Autophosphorylation of the catalytic subunit of the DNA-dependent protein kinase is required for efficient end processing during DNA double-strand break repair. Mol Cell Biol 23, 5836–5848 (2003)

  • [38]Y.V.R. Reddy, Q. Ding, S.P. Lees-Miller, K. Meek, D.A. Ramsden, Non-homologous end joining requires that the DNA-PK complex undergo an autophosphorylation-dependent rearrangement at DNA ends. J Biol Chem 279, 39408–39413 (2004)

  • [39]M. Hammel, Y. Yu, B.L. Mahaney, B. Cai, R. Ye, B.M. Phipps, R.P. Rambo, G.L. Hura, M. Pelikan, S. So, R.M. Abolfath, D.J. Chen, S.P. Lees-Miller, J.P. Tainer, Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex. J Biol Chem 285, 1414–1423 (2010)

  • [40]Y. Yu, W. Wang, Q. Ding, R. Ye, D. Chen, D. Merkle, D. Schriemer, K. Meek, S.P. Lees-Miller, DNA-PK phosphorylation sites in XRCC4 are not required for survival after radiation or for V(D)J recombination. DNA Repair (Amst.) 2, 1239–1252 (2003)

  • [41]P.-O. Mari, B.I. Florea, S.P. Persengiev, N.S. Verkaik, H.T. Brüggenwirth, M. Modesti, G. Giglia-Mari, K. Bezstarosti, J.A. Demmers, T.M Luider, A.B. Houtsmuller, D.C. van Gent, Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4 Proc Natl Acad Sci U S A 103, 18597–18602 (2006)

  • [42]P. Reynolds, J.A. Anderson, J.V. Harper, M.A. Hill, S.W. Botchway, A.W. Parker, P. O’Neill, The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage. Nucleic Acids Res 40, 10821–10831 (2012)

  • [43]B. Li, L. Comai, Requirements for the nucleolytic processing of DNA ends by the Werner syndrome protein-Ku70/80 complex. J Biol Chem 276, 9896–9902 (2001)

  • [44]P. Karmakar, C.M. Snowden, D.A. Ramsden, V.A. Bohr, Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus. Nucleic Acids Res 30, 3583–3591 (2002)

  • [45]P. Karmakar, J. Piotrowski, R.M. Brosh, J.A. Sommers, S.P.L. Miller, W.-H. Cheng, C.M. Snowden, D.A. Ramsden, V.A. Bohr, Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation. J Biol Chem 277, 18291–18302 (2002)

  • [46]S. Parvathaneni, A. Stortchevoi, J.A. Sommers, R.M. Brosh, S. Sharma, Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks. PLoS One 8, e62481 (2013)

  • [47]R.A. Shamanna, D.K. Singh, H. Lu, G. Mirey, G. Keijzers, B. Salles, D.L. Croteau, V.A. Bohr, RECQ helicase RECQL4 participates in non-homologous end joining and interacts with the Ku complex. Carcinogenesis 35, 2415–2424 (2014)

  • [48]R. Kusumoto-Matsuo, P.L. Opresko, D. Ramsden, H. Tahara, V.A. Bohr, Cooperation of DNA-PKcs and WRN helicase in the maintenance of telomeric D-loops. Aging (Albany NY) 2, 274–284 (2010)

  • [49]R. Kusumoto, L. Dawut, C. Marchetti, J. Wan Lee, A. Vindigni, D. Ramsden, V.A. Bohr, Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing. Biochemistry 47, 7548–7556 (2008)

  • [50]R. Kusumoto-Matsuo, D. Ghosh, P. Karmakar, A. May, D. Ramsden, V.A. Bohr, Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks. Aging (Albany NY) 6, 70–81 (2014)

  • [51]G. Keijzers, S. Maynard, R.A. Shamanna, L.J. Rasmussen, D.L. Croteau, V.A. Bohr, The role of RecQ helicases in non-homologous end-joining. Crit Rev Biochem Mol Biol 49, 463–472 (2014)

  • [52]G. Keijzers, V.A. Bohr, L.J. Rasmussen, Human exonuclease 1 (EXO1) activity characterization and its function on FLAP structures. Biosci Rep (2015)

  • [53]A.V. Nimonkar, J. Genschel, E. Kinoshita, P. Polaczek, J.L. Campbell, C. Wyman, P. Modrich, S.C. Kowalczykowski, BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev 25, 350–362 (2011)

  • [54]N. Tomimatsu, B. Mukherjee, K. Deland, A. Kurimasa, E. Bolderson, K.K. Khanna, S. Burma, Exo1 plays a major role in DNA end resection in humans and influences double-strand break repair and damage signaling decisions. DNA Repair (Amst.) 11, 441–448 (2012)

  • [55]K.-I. Yano, K. Morotomi-Yano, S.-Y. Wang, N. Uematsu, K.-J. Lee, A. Asaithamby, E. Weterings, D.J.Chen, Ku recruits XLF to DNA double-strand breaks. EMBO Rep 9, 91–96 (2008)

  • [56]G.J. Grundy, S.L. Rulten, Z. Zeng, R. Arribas-Bosacoma, N. Iles, K. Manley, A. Oliver, K.W. Caldecott, APLF promotes the assembly and activity of non-homologous end joining protein complexes. Embo J 32, 112–125 (2013)

  • [57]E. Riballo, L. Woodbine, T. Stiff, S.A. Walker, A.A. Goodarzi, P.A. Jeggo, XLF-Cernunnos promotes DNA ligase IV-XRCC4 re-adenylation following ligation. Nucleic Acids Res 37, 482–492 (2009)

  • [58]J.M. Jones, M. Gellert, W. Yang, A Ku bridge over broken DNA. Structure 9, 881–884 (2001)

  • [59]T. Mimori, J.A. Hardin, Mechanism of interaction between Ku protein and DNA. J Biol Chem 261, 10375–10379 (1986)

  • [60]S. Yoo, A. Kimzey, W.S. Dynan, Photocross-linking of an oriented DNA repair complex. Ku bound at a single DNA end. J Biol Chem 274, 20034–20039 (1999)

  • [61]D. Pang, S. Yoo, W.S. Dynan, M. Jung, A. Dritschilo, Ku proteins join DNA fragments as shown by atomic force microscopy. Cancer Res 57, 1412–1415 (1997)

  • [62]R.B. Cary, S.R. Peterson, J. Wang, D.G. Bear, E.M. Bradbury, D.J. Chen, DNA looping by Ku and the DNA-dependent protein kinase. Proc Natl Acad Sci U S A 94, 4267–4272 (1997)

  • [63]M. Yaneva, T. Kowalewski, M.R. Lieber, Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy studies. Embo J 16, 5098–5112 (1997)

  • [64]M. Falzon, J.W. Fewell, E.L. Kuff, EBP-80, a transcription factor closely resembling the human autoantigen Ku, recognizes single-to double-strand transitions in DNA. J Biol Chem 268, 10546–10552 (1993)

  • [65]M. Ono, P.W. Tucker, J.D. Capra, Production and characterization of recombinant human Ku antigen. Nucleic Acids Res 22, 3918–3924 (1994)

  • [66]P.R. Blier, A.J. Griffith, J. Craft, J.A. Hardin, Binding of Ku protein to DNA. Measurement of affinity for ends and demonstration of binding to nicks. J Biol Chem 268, 7594–7601 (1993)

  • [67]W.S. Dynan, S. Yoo, Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res 26, 1551–1559 (1998)

  • [68]J.A. Downs, S.P. Jackson, A means to a DNA end: the many roles of Ku. Nat Rev Mol Cell Biol 5, 367–378 (2004)

  • [69]D. Ristic, M. Modesti, R. Kanaar, C. Wyman, Rad52 and Ku bind to different DNA structures produced early in double-strand break repair. Nucleic Acids Res 31, 5229–5237 (2003)

  • [70]L. Aravind, E.V. Koonin, SAP - a putative DNA-binding motif involved in chromosomal organization. Trends Biochem Sci 25, 112–114 (2000)

  • [71]Z. Zhang, L. Zhu, D. Lin, F. Chen, D.J. Chen, Y. Chen, The three-dimensional structure of the C-terminal DNA-binding domain of human Ku70. J Biol Chem 276, 38231–38236 (2001)

  • [72]Z. Zhang, W. Hu, L. Cano, T.D. Lee, D.J. Chen, Y. Chen, Solution structure of the C-terminal domain of Ku80 suggests important sites for protein-protein interactions. Structure 12, 495–502 (2004)

  • [73]J.A. Lehman, D.J. Hoelz, J.J. Turchi, DNA-dependent conformational changes in the Ku heterodimer. Biochemistry 47, 4359–4368 (2008)

  • [74]S. Hu, J.M. Pluth, F.A. Cucinotta, Putative binding modes of Ku70-SAP domain with double strand DNA: a molecular modeling study. J Mol Model 18, 2163–2174 (2012)

  • [75]R. Harris, D. Esposito, A. Sankar, J.D. Maman, J.A. Hinks, L.H. Pearl, P.C. Driscoll, The 3D solution structure of the C-terminal region of Ku86 (Ku86CTR). J Mol Biol 335, 573–582 (2004)

  • [76]D. Gell, S.P. Jackson, Mapping of protein-protein interactions within the DNA-dependent protein kinase complex. Nucleic Acids Res 27, 3494–3502 (1999)

  • [77]B.K. Singleton, M.I. Torres-Arzayus, S.T. Rottinghaus, G.E. Taccioli, P.A. Jeggo, The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit. Mol Cell Biol 19, 3267–3277 (1999)

  • [78]E. Weterings, N.S. Verkaik, G. Keijzers, B.I. Florea, S.-Y. Wang, L.G. Ortega, N. Uematsu, D.J. Chen, D.C. van Gent, The Ku80 carboxy terminus stimulates joining and artemis-mediated processing of DNA ends. Mol Cell Biol 29, 1134–1142 (2009)

  • [79]S.M. Bennett, T.M. Neher, A. Shatilla, J.J. Turchi, Molecular analysis of Ku redox regulation. BMC Mol Biol 10, 86 (2009)

  • [80]V.L. Fell, C. Schild-Poulter, Ku regulates signaling to DNA damage response pathways through the Ku70 von Willebrand A domain. Mol Cell Biol 32, 6–87 (2012)

  • [81]A.A. Bertuch, V. Lundblad, The Ku heterodimer performs separable activities at double-strand breaks and chromosome termini. Mol Cell Biol 23, 8202–8215 (2003)

  • [82]A. Nussenzweig, C. Chen, V. da Costa Soares, M. Sanchez, K. Sokol, M.C. Nussenzweig, G.C. Li, Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 382, 551–555 (1996)

  • [83]Y. Gu, K.J. Seidl, G.A. Rathbun, C. Zhu, J.P. Manis, N. van der Stoep, L. Davidson, H.L. Cheng, J.M. Sekiguchi, K. Frank, P. Stanhope-Baker, M.S. Schlissel, D.B. Roth, F.W. Alt, Growth Retardation and Leaky SCID Phenotype of Ku70-Deficient Mice. Immunity 7, 653–665 (1997)

  • [84]A. Nussenzweig, K. Sokol, P. Burgman, L. Li, G.C. Li, Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: The effects of ionizing radiation on growth, survival, anddevelopment. Proc Natl Acad Sci U S A 94, 13588-13593 (1997)

  • [85]H. Ouyang, A. Nussenzweig, A. Kurimasa, V.D.C. Soares, X. Li, C. Cordon-Cardo, W.H. Li, N. Cheong, M. Nussenzweig, G. Iliakis, D.J. Chen G.C. Li, Ku70 Is Required for DNA Repair but Not for T Cell Antigen Receptor Gene Recombination In vivo. J Exp Med 186, 921–929 (1997)

  • [86]F.J. Fattah, N.F. Lichter, K.R. Fattah, S. Oh, E.A. Hendrickson, Ku70, an essential gene, modulates the frequency of rAAV-mediated gene targeting in human somatic cells. Proc Natl Acad Sci U S A 105, 8703–8708 (2008)

  • [87]K.R. Fattah, B.L. Ruis, E.A. Hendrickson, Mutations to Ku reveal differences in human somatic cell lines. DNA Repair (Amst.) 7, 762–774 (2008)

  • [88]Y. Wang, G. Ghosh, E.A. Hendrickson, Ku86 represses lethal telomere deletion events in human somatic cells. Proc Natl Acad Sci U S A 106, 12430–12435 (2009)

  • [89]M. Korabiowska, T. Quentin, T. Schlott, H. Bauer, E. Kunze, Down-regulation of Ku 70 and Ku 80 mRNA expression in transitional cell carcinomas of the urinary bladder related to tumor progression. World J Urol 22, 431–440 (2004)

  • [90]M. Korabiowska, J. Voltmann, J.F. Hönig, P. Bortkiewicz, F. König, C. Cordon-Cardo, F. Jenckel, P. Ambrosch, G. Fischer, Altered expression of DNA double-strand repair genes Ku70 and Ku80 in carcinomas of the oral cavity. Anticancer Res 26, 2101–2105 (2006)

  • [91]M. Korabiowska, C. Cordon-Cardo, M. Schinagl, M. Karaus, J. Stachura, H. Schulz, G. Fischer, Loss of Ku70/Ku80 expression occurs more frequently in hereditary than in sporadic colorectal tumors. Tissue microarray study. Hum Pathol 37, 448–452 (2006)

  • [92]Y. Lu, J. Gao, Y. Lu, Downregulated Ku70 and ATM associated to poor prognosis in colorectal cancer among Chinese patients. Onco Targets Ther 7, 1955–1961 (2014)

  • [93]P. Willems, K. De Ruyck, R. Van den Broecke, A. Makar, G. Perletti, H. Thierens, A. Vral, A polymorphism in the promoter region of Ku70/XRCC6, associated with breast cancer risk and oestrogen exposure. J Cancer Res Clin Oncol 135, 1159–1168 (2009)

  • [94]W. He, S. Luo, T. Huang, J. Ren, X. Wu, J. Shao, Q. Zhu, The Ku70 -1310C/G promoter polymorphism is associated with breast cancer susceptibility in Chinese Han population. Mol Biol Rep 39, 577–583 (2012)

  • [95]Y.P. Fu, J.C. Yu, T.C. Cheng, M.A. Lou, G.C. Hsu, C.Y. Wu, S.T. Chen, H.S. Wu, P.E. Wu. C.Y. Shen, Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res 63, 2440–2446 (2003)

  • [96]J.Q. Li, J. Chen, N.N. Liu, L. Yang, Y. Zeng, B. Wang, X.R. Wang, Ku80 gene G-1401T promoter polymorphism and risk of gastric cancer. World J Gastroenterol 17, 2131–2136 (2011)

  • [97]L. Postow, C. Ghenoiu, E.M. Woo, A.N. Krutchinsky, B.T. Chait, H. Funabiki, Ku80 removal from DNA through double strand break-induced ubiquitylation. J Cell Biol 182, 467–479 (2008)

  • [98]J. Herrmann, L.O. Lerman, A. Lerman, Ubiquitin and ubiquitin-like proteins in protein regulation. Circ Res 1276–1291 (2007)

  • [99]J.A. Sommers, A.N. Suhasini, R.M. Brosh, Protein Degradation Pathways Regulate the Functions of Helicases in the DNA Damage Response and Maintenance of Genomic Stability. Biomolecules 5, 590–616 (2015)

  • [100]W. Zhou, W. Wei, Y. Sun, Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases. Cell Res 23, 599–619 (2013)

  • [101]N. Mailand, S. Bekker-Jensen, H. Faustrup, F. Melander, J. Bartek, C. Lukas, J. Lukas, RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887–900 (2007)

  • [102]S. Panier, D. Durocher, Regulatory ubiquitylation in response to DNA double-strand breaks. DNA Repair (Amst.) 8, 436–443 (2009)

  • [103]S. Bhutani, A. Das, M. Maheshwari, S.C. Lakhotia, N.R. Jana, Dysregulation of core components of SCF complex in poly-glutamine disorders. Cell Death Dis 3, e428 (2012)

  • [104]J. Jones, K. Wu, Y. Yang, C. Guerrero, N. Nillegoda, Z.-Q. Pan, L. Huang, A targeted proteomic analysis of the ubiquitin-like modifier nedd8 and associated proteins. J Proteome Res 7, 1274–1287 (2008)

  • [105]J.S. Brown, S.P. Jackson, Ubiquitylation, neddylation and the DNA damage response. Open Biol 5, (2015)

  • [106]F. Osaka, M. Saeki, S. Katayama, N. Aida, A. Toh-E, K. Kominami, T. Tado, T. Suszuki, T. Chiba, K. Tanaka, S. Kato, Covalent modifier NEDD8 is essential for SCF ubiquitin-ligase in fission yeast. Embo J 19, 3475–3484 (2000)

  • [107]G.T.-M. Lok, S.M.-H. Sy, S.-S. Dong, Y.-P. Ching, S.W. Tsao, T.M. Thomson, M.S. Huen, Differential regulation of RNF8-mediated Lys48-and Lys63-based poly-ubiquitylation. Nucleic Acids Res 40, 196–205 (2012)

  • [108]M.H. Peuscher, J.J.L. Jacobs, DNA-damage response and repair activities at uncapped telomeres depend on RNF8. Nat Cell Biol 13, 1139–1145 (2011)

  • [109]M. Bohgaki, T. Bohgaki, S. El Ghamrasni, T. Srikumar, G. Maire, S. Panier, A. Fradet-Turcotte, G.S. Stewart, B. Raught, A. Hakem, R. Hakem, RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks. Proc Natl Acad Sci U S A 110, 20982–20987 (2013)

  • [110]L. Postow, H. Funabiki, An SCF complex containing Fbxl12 mediates DNA damage-induced Ku80 ubiquitylation. Cell Cycle 12, 587–595 (2013)

  • [111]B. Vaz, S. Halder, K. Ramadan, Role of p97/VCP (Cdc48) in genome stability. Front Genet 4, 1-14 (2013)

  • [112]S. Bergink, T. Ammon, M. Kern, L. Schermelleh, H. Leonhardt, S. Jentsch, Role of Cdc48/p97 as a SUMO-targeted segregase curbing Rad51-Rad52 interaction. Nat Cell Biol 15, 526–532 (2013)

  • [113]J.S. Brown, N. Lukashchuk, M. Sczaniecka-Clift, S. Britton, C. le Sage, P. Calsou, P. Beli, Y. Galanty, S.P. Jackson, Neddylation Promotes Ubiquitylation and Release of Ku from DNA-Damage Sites. Cell Rep 11, 704–714 (2015)

  • [114]L. Feng, J. Chen, The E3 ligase RNF8 regulates KU80 removal and NHEJ repair. Nat Struct Mol Biol 19, 201–206 (2012)

  • [115]D.K. Singh, P. Karmakar, M. Aamann, S.H. Schurman, A. May, D.L. Croteau, L. Burks, S.E. Plon, V.A. Bohr, The involvement of human RECQL4 in DNA double-strand break repair. Aging Cell 9, 358–371 (2010)

  • [116]V. Popuri, M. Ramamoorthy, T. Tadokoro, D.K. Singh, P. Karmakar, D.L. Croteau, V.A. Bohr, Recruitment and retention dynamics of RECQL5 at DNA double strand break sites. DNA Repair (Amst.) 11, 624–635 (2012)

  • [117]S. Panier, S.J. Boulton, Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol 15, 7–18 (2014)

  • [118]A.K. Jain, M.C. Barton, Making sense of ubiquitin ligases that regulate p53. Cancer Biol Ther 10, 665–672 (2010)

  • [119]F. Kriegenburg, V. Jakopec, E.G. Poulsen, S.V. Nielsen, A. Roguev, N. Krogan, C. Gordon, U. Fleig, R. Hartmann-Petersen, A chaperone-assisted degradation pathway targets kinetochore proteins to ensure genome stability. PLoS Genet 10, e1004140 (2014)

  • [120]K.I. Nakayama, K. Nakayama, Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6, 369–381 (2006)

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Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

1 Jan 2016Review

The Ku70/80 ring in Non-Homologous End-Joining: easy to slip on, hard to remove

Birthe B. Kragelund 1, Eric Weterings 2, Rasmus Hartmann-Petersen 1, Guido Keijzers 3,*
Affiliations
Article Info

1 Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark

2 Department of Radiation Oncology, University of Arizona, 1501 N. Campbell Ave, Tucson, Arizona 85724, USA

3 Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark

Abstract

Non-homologous end-joining (NHEJ) is an essential DNA double strand break repair pathway during all cell cycle stages. Deficiency in NHEJ factors can lead to accumulation of unrepaired DNA breaks or faulty DNA repair, which may ultimately result in cell death, senescence or carcinogenesis. The Ku70/80 heterodimer is a key-player in the NHEJ pathway and binds to DNA termini with high affinity, where it helps to protect DNA ends from degradation and to recruit other NHEJ factors required for repair. The mechanism of Ku70/80 detachment from the DNA helix after completion of DNA repair is incompletely understood. Some data suggest that certain DNA repair factors are ubiquitylated and targeted for proteasomal degradation after repair. Recent studies suggest that Ku80 is conjugated to lysine48-linked ubiquitin chains by the Skp1-Cullin-F-box (SCF) complex and/or the RING finger protein 8 (RNF8) ubiquitin-protein ligases, followed by rapid proteasomal degradation. In this review we address the structure and function of the Ku70/80 heterodimer and how ubiquitylation may affect the release of Ku70/80 from chromatin and its subsequent degradation via the ubiquitin-proteasome system.

Keywords

  • Ku70
  • Ku80
  • Degradation
  • Double strand break
  • NEDD8
  • Non-homologous end-joining
  • NHEJ
  • SCF
  • RNF8
  • Proteasome
  • Ubiquitylation
  • Review

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