Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining

Biochemical Journal

Volumn 417, Issue 3, 2009, Pages 639-650

  Mahaney, Brandi L ^a   Meek, Katheryn ^b   Lees Miller, Susan P ^a,b  

^a UNIVERSITY OF CALGARY   (Canada)

^b MICHIGAN STATE UNIVERSITY   (United States)

Author keywords

DNA double strand break repair; DNA dependent protein kinase (DNA PK); Ionizing radiation; Non homologous end joining; Phosphorylation

Indexed keywords

ARTEMIS; BIOLOGICAL PROCESS; CATALYTIC SUBUNITS; CHEMOTHERAPEUTIC DRUGS; CHINESE HAMSTERS; CHROMOSOMAL TRANSLOCATIONS; CYTOTOXIC; DNA LESIONS; DNA POLYMERASE; DNA-DEPENDENT PROTEIN KINASE; DNA-DEPENDENT PROTEIN KINASE (DNA-PK); DOUBLE-STRAND BREAKS; EXTERNAL SOURCES; GENOMIC INSTABILITY; HELICASE; HETERODIMER; MAMMALIAN CELLS; NON-HOMOLOGOUS END-JOINING; POLYNUCLEOTIDE; TOPOISOMERASE POISON;

CELL DEATH; DNA; GENES; IONIZING RADIATION; JOINING; MAMMALS; PHOSPHORYLATION; PROTEINS; RADIATION SHIELDING; RADIOACTIVITY; REPAIR;

NUCLEIC ACIDS;

ARTEMIS; DEOXYRIBONUCLEOPROTEIN; DNA DEPENDENT PROTEIN KINASE; DNA POLYMERASE; DNA POLYMERASE LAMBDA; DNA POLYMERASE MU; KU ANTIGEN; POLYDEOXYRIBONUCLEOTIDE SYNTHASE; POLYNUCLEOTIDE 5' HYDROXYL KINASE; PROTEIN APLF; PROTEIN KINASE C; PROTEIN XLF; UNCLASSIFIED DRUG; WERNER SYNDROME PROTEIN; XRCC4 PROTEIN;

DNA REPAIR; DOUBLE STRANDED DNA BREAK; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; HUMAN; IONIZING RADIATION; MAMMAL CELL; NON HOMOLOGOUS END JOINING; NONHUMAN; PRIORITY JOURNAL; PROCESS DESIGN; PROTEIN DNA INTERACTION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REVIEW; ANIMAL; BIOLOGICAL MODEL; DNA DAMAGE; GENETICS; METABOLISM;

CRICETULUS GRISEUS; MAMMALIA;

ANIMALS; DNA BREAKS, DOUBLE-STRANDED; DNA DAMAGE; DNA REPAIR; DNA REPAIR ENZYMES; DNA-ACTIVATED PROTEIN KINASE; HUMANS; MODELS, BIOLOGICAL; RADIATION, IONIZING;

EID: 59849089955     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BJ20080413     Document Type: Review

References (184)

1. Povirk, L. F. (2006) Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks. DNA Repair 5, 1199-1212
2. Helleday, T., Lo, J., van Gent, D. C. and Engelward, B. P. (2007) DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair 6, 923-935
3. Kastan, M. B. and Bartek, J. (2004) Cell-cycle checkpoints and cancer. Nature 432, 316-323
4. Lobrich, M. and Jeggo, P. A. (2007) The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat. Rev. Cancer 7, 861-869
5. Hoeijmakers, J. H. (2001) Genome maintenance mechanisms for preventing cancer. Nature 411, 366-374
6. Dianov, G. L. and Parsons, J. L. (2007) Co-ordination of DNA single strand break repair. DNA Repair 6, 454-460
7. Almeida, K. H. and Sobol, R. W. (2007) A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification. DNA Repair 6, 695-711
8. Friedberg, E. C., Walker, G. C., Siede, W., Wood, R. D., Schultz, R. A. and Ellenberger, T. (2005) DNA Repair and Mutagenesis, ASM Press, Washington, D.C.
9. Dianov, G. L., O'Neill, P. and Goodhead, D. T. (2001) Securing genome stability by orchestrating DNA repair: removal of radiation-induced clustered lesions in DNA. BioEssays 23, 745-749
10. Lieber, M. R., Yu, K. and Raghavan, S. C. (2006) Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair 5, 1234-1245
11. Branzei, D. and Foiani, M. (2008) Regulation of DNA repair throughout the cell cycle. Nat. Rev. Mol. Cell Biol. 9, 297-308
12. Rothkamm, K., Kruger, I., Thompson, L. H. and Lobrich, M. (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol. Cell. Biol. 23, 5706-5715
13. Windhofer, F., Wu, W., Wang, M., Singh, S. K., Saha, J., Rosidi, B. and Iliakis, G. (2007) Marked dependence on growth state of backup pathways of NHEJ. Int. J. Radiat. Oncol. Biol. Phys. 68, 1462-1470
14. Windhofer, F., Wu, W. and Iliakis, G. (2007) Low levels of DNA ligases III and IV sufficient for effective NHEJ. J. Cell. Physiol. 213, 475-483
15. Wang, H., Rosidi, B., Perrault, R., Wang, M., Zhang, L., Windhofer, F. and Iliakis, G. (2005) DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res. 65, 4020-4030
16. Audebert, M., Salles, B. and Calsou, P. (2004) Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J. Biol. Chem. 279, 55117-55126
17. Yan, C. T., Boboila, C., Souza, E. K., Franco, S., Hickernell, T. R., Murphy, M., Gumaste, S., Geyer, M., Zarrin, A. A., Manis, J. P. et al. (2007) IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449, 478-482
18. Bassing, C. H. and Alt, F. W. (2004) The cellular response to general and programmed DNA double strand breaks. DNA Repair 3, 781-796
19. O'Driscoll, M. and Jeggo, P. A. (2006) The role of double-strand break repair: insights from human genetics. Nat. Rev. Genet. 7, 45-54
20. Meek, K., Dang, V. and Lees Miller, S. P. (2009) DNA-PK: the means to justify the ends? Adv. Immunol., in the press
21. Meek, K., Gupta, S., Ramsden, D. A. and Lees-Miller, S. P. (2004) The DNA-dependent protein kinase: the director at the end. Immunol. Rev. 200, 132-141
22. Kurimasa, A., Kumano, S., Boubnov, N. V., Story, M. D., Tung, C. S., Peterson, S. R. and Chen, D. J. (1999) Requirement for the kinase activity of human DNA-dependent protein kinase catalytic subunit in DNA strand break rejoining. Mol. Cell. Biol. 19, 3877-3884
23. Kienker, L. J., Shin, E. K. and Meek, K. (2000) Both V(D)J recombination and radioresistance require DNA-PK kinase activity, though minimal levels suffice for V(D)J recombination. Nucleic Acids Res. 28, 2752-2761
24. Walker, J. R., Corpina, R. A. and Goldberg, J. (2001) Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607-614
25. Chan, D. W., Ye, R., Veillette, C. J. and Lees-Miller, S. P. (1999) DNA-dependent protein kinase phosphorylation sites in Ku 70/80 heterodimer. Biochemistry 38, 1819-1828
26. Lees-Miller, S. P. and Meek, K. (2003) Repair of DNA double strand breaks by non-homologous end joining. Biochimie 85, 1161-1173
27. Harris, R., Esposito, D., Sankar, A., Maman, J. D., Hinks, J. A., Pearl, L. H. and Driscoll, P. C. (2004) The 3D solution structure of the C-terminal region of Ku86 (Ku86CTR). J. Mol. Biol. 335, 573-582
28. Zhang, Z., Hu, W., Cano, L., Lee, T. D., Chen, D. J. and Chen, Y. (2004) Solution structure of the C-terminal domain of Ku80 suggests important sites for protein-protein interactions. Structure 12, 495-502
29. Falck, J., Coates, J. and Jackson, S. P. (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605-611
30. Gell, D. and Jackson, S. P. (1999) Mapping of protein-protein interactions within the DNA-dependent protein kinase complex. Nucleic Acids Res. 27, 3494-3502
31. Singleton, B. K., Torres-Arzayus, M. I., Rottinghaus, S. T., Taccioli, G. E. and Jeggo, P. A. (1999) The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit. Mol. Cell. Biol. 19, 3267-3277
32. Downs, J. A. and Jackson, S. P. (2004) A means to a DNA end: the many roles of Ku. Nat. Rev. Mol. Cell Biol. 5, 367-378
33. Cary, R. B., Peterson, S. R., Wang, J., Bear, D. G., Bradbury, E. M. and Chen, D. J. (1997) DNA looping by Ku and the DNA-dependent protein kinase. Proc. Natl. Acad. Sci. U.S.A. 94, 4267-4272
34. Yoo, S. and Dynan, W. S. (1999) Geometry of a complex formed by double strand break repair proteins at a single DNA end: recruitment of DNA-PKcs induces inward translocation of Ku protein. Nucleic Acids Res. 27, 4679-4686
35. Kim, J. S., Krasieva, T. B., Kurumizaka, H., Chen, D. J., Taylor, A. M. and Yokomori, K. (2005) Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells. J. Cell Biol. 170, 341-347
36. 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. et al. (2006) Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4. Proc. Natl. Acad. Sci. U.S.A. 103, 18597-18602
37. Weterings, E. and Chen, D. J. (2007) DNA-dependent protein kinase in nonhomologous end joining: a lock with multiple keys? J. Cell Biol. 179, 183-186
38. Costantini, S., Woodbine, L., Andreoli, L., Jeggo, P. A. and Vindigni, A. (2007) Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK. DNA Repair 6, 712-722
39. Nick McElhinny, S. A., Snowden, C. M., McCarville, J. and Ramsden, D. A. (2000) Ku recruits the XRCC4-ligase IV complex to DNA ends. Mol. Cell. Biol. 20, 2996-3003
40. Yano, K., Morotomi-Yano, K., Wang, S. Y., Uematsu, N., Lee, K. J., Asaithamby, A., Weterings, E. and Chen, D. J. (2008) Ku recruits XLF to DNA double-strand breaks. EMBO Rep. 9, 91-96
41. Mahajan, K. N., Nick McElhinny, S. A., Mitchell, B. S. and Ramsden, D. A. (2002) Association of DNA polymerase μ (pol μ) with Ku and ligase IV: role for pol μ in end-joining double-strand break repair. Mol. Cell. Biol. 22, 5194-5202
42. Ma, Y., Lu, H., Tippin, B., Goodman, M. F., Shimazaki, N., Koiwai, O., Hsieh, C. L., Schwarz, K. and Lieber, M. R. (2004) A biochemically defined system for mammalian nonhomologous DNA end joining. Mol. Cell 16, 701-713
43. Gottlieb, T. M. and Jackson, S. P. (1993) The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72, 131-142
44. Yano, K. and Chen, D. J. (2008) Live cell imaging of XLF and XRCC4 reveals a novel view of protein assembly in the non-homologous end-joining pathway. Cell Cycle 7, 1321-1325
45. Lehman, J. A., Hoelz, D. J. and Turchi, J. J. (2008) DNA-dependent conformational changes in the Ku heterodimer. Biochemistry 47, 4359-4368
46. Uematsu, N., Weterings, E., Yano, K., Morotomi-Yano, K., Jakob, B., Taucher-Scholz, G., Mari, P. O., van Gent, D. C., Chen, B. P. and Chen, D. J. (2007) Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks. J. Cell Biol. 177, 219-229
47. Abraham, R. T. (2004) PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. DNA Repair 3, 883-887
48. Gupta, S. and Meek, K. (2005) The leucine-rich region of DNA-PKcs contributes to its innate DNA affinity. Nucleic Acids Res. 33, 6972-6981
49. Perry, J. and Kleckner, N. (2003) The ATRs, ATMs, and TORs are giant HEAT repeat proteins. Cell 112, 151-155
50. Jin, S., Kharbanda, S., Mayer, B., Kufe, D. and Weaver, D. T. (1997) Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit. J. Biol. Chem. 272, 24763-24766
51. Mordes, D. A., Glick, G. G., Zhao, R. and Cortez, D. (2008) TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev. 22, 1478-1489
52. Suwa, A., Hirakata, M., Takeda, Y., Jesch, S. A., Mimori, T. and Hardin, J. A. (1994) DNA-dependent protein kinase (Ku protein-p350 complex) assembles on double-stranded DNA. Proc. Natl. Acad. Sci. U.S.A. 91, 6904-6908
53. DeFazio, L. G., Stansel, R. M., Griffith, J. D. and Chu, G. (2002) Synapsis of DNA ends by DNA-dependent protein kinase. EMBO J. 21, 3192-3200
54. Meek, K., Douglas, P., Cui, X., Ding, Q. and Lees-Miller, S. P. (2007) trans-Autophosphorylation at DNA-dependent protein kinase's two major autophosphorylation site clusters facilitates end processing but not end joining. Mol. Cell. Biol. 27, 3881-3890
55. Lees-Miller, S. P., Sakaguchi, K., Ullrich, S. J., Appella, E. and Anderson, C. W. (1992) Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53. Mol. Cell. Biol. 12, 5041-5049
56. O'Neill, T., Dwyer, A. J., Ziv, Y., Chan, D. W., Lees-Miller, S. P., Abraham, R. H., Lai, J. H., Hill, D., Shiloh, Y., Cantley, L. C. and Rathbun, G. A. (2000) Utilization of oriented peptide libraries to identify substrate motifs selected by ATM. J. Biol. Chem. 275, 22719-22727
57. Douglas, P., Sapkota, G. P., Morrice, N., Yu, Y., Goodarzi, A. A., Merkle, D., Meek, K., Alessi, D. R. and Lees-Miller, S. P. (2002) Identification of in vitro and in vivo phosphorylation sites in the catalytic subunit of the DNA-dependent protein kinase. Biochem. J. 368, 243-251
58. Yu, Y., Wang, W., Ding, Q., Ye, R., Chen, D., Merkle, D., Schriemer, D., Meek, K. and Lees-Miller, S. P. (2003) DNA-PK phosphorylation sites in XRCC4 are not required for survival after radiation or for V(D)J recombination. DNA Repair 2, 1239-1252
59. Yu, Y., Mahaney, B. L., Yano, K. I., Ye, R., Fang, S., Douglas, P., Chen, D. J. and Lees-Miller, S. P. (2008) DNA-PK and ATM phosphorylation sites in XLF/Cernunnos are not required for repair of DNA double strand breaks. DNA Repair 7, 1680-1692
60. O'Connor, M. J., Martin, N. M. and Smith, G. C. (2007) Targeted cancer therapies based on the inhibition of DNA strand break repair. Oncogene 26, 7816-7824
61. Zhao, Y., Thomas, H. D., Batey, M. A., Cowell, I. G., Richardson, C. J., Griffin, R. J., Calvert, A. H., Newell, D. R., Smith, G. C. and Curtin, N. J. (2006) Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 66, 5354-5362
62. Goodarzi, A. A.,Yu,Y.,Riballo, E., Douglas,P.,Walker,S. A.,Ye,R., Harer, C., Marchetti, C., Morrice, N., Jeggo, P. A. and Lees-Miller, S. P. (2006) DNA-PK autophosphorylation facilitates Artemis endonuclease activity. EMBO J. 25, 3880-3889
63. Douglas, P., Gupta, S., Morrice, N., Meek, K. and Lees-Miller, S. P. (2005) DNA-PK-dependent phosphorylation of Ku70/80 is not required for non-homologous end joining. DNA Repair 4, 1006-1018
64. Wang, Y. G., Nnakwe, C., Lane, W. S., Modesti, M. and Frank, K. M. (2004) Phosphorylation and regulation of DNA ligase IV stability by DNA-dependent protein kinase. J. Biol. Chem. 279, 37282-37290
65. Ma, Y., Pannicke, U., Lu, H., Niewolik, D., Schwarz, K. and Lieber, M. R. (2005) The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis. J. Biol. Chem. 280, 33839-33846
66. Chen, B. P., Chan, D. W., Kobayashi, J., Burma, S., Asaithamby, A., Morotomi-Yano, K., Botvinick, E., Qin, J. and Chen, D. J. (2005) Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double strand breaks. J. Biol. Chem. 280, 14709-14715
67. Chan, D. W., Chen, B. P., Prithivirajsingh, S., Kurimasa, A., Story, M. D., Qin, J. and Chen, D. J. (2002) Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev. 16, 2333-2338
68. Ding, Q., Reddy, Y. V., Wang, W., Woods, T., Douglas, P., Ramsden, D. A., Lees-Miller, S. P. and Meek, K. (2003) 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
69. Douglas, P., Cui, X., Block, W. D., Yu, Y., Gupta, S., Ding, Q., Ye, R., Morrice, N., Lees-Miller, S. P. and Meek, K. (2007) The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is phosphorylated in vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain. Mol. Cell. Biol. 27, 1581-1591
70. Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, 3rd, E. R., Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y. et al. (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160-1166
71. Chen, B. P.-C., Uematsu, N., Kobayashi, J., Lerenthal, Y., Krempler, A., Yajima, H., Lobrich, M., Shiloh, Y. and Chen, D. J. (2007) ATM is essential for DNA-PKcs phosphorylation at T2609 cluster upon DNA double strand break. J. Biol. Chem. 282, 6582-6587
72. Yajima, H., Lee, K. J. and Chen, B. P. (2006) ATR-dependent phosphorylation of DNA-dependent protein kinase catalytic subunit in response to UV-induced replication stress. Mol. Cell. Biol. 26, 7520-7528
73. Olsen, J. V., Blagoev, B., Gnad, F., Macek, B., Kumar, C., Mortensen, P. and Mann, M. (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635-648
74. Beausoleil, S. A., Jedrychowski, M., Schwartz, D., Elias, J. E., Villen, J., Li, J., Cohn, M. A., Cantley, L. C. and Gygi, S. P. (2004) Large-scale characterization of HeLa cell nuclear phosphoproteins. Proc. Natl. Acad. Sci. U.S.A. 101, 12130-12135
75. Merkle, D., Douglas, P., Moorhead, G. B., Leonenko, Z., Yu, Y., Cramb, D., Bazett-Jones, D. P. and Lees-Miller, S. P. (2002) The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation. Biochemistry 41, 12706-12714
76. Chan, D. W. and Lees-Miller, S. P. (1996) The DNA-dependent protein kinase is inactivated by autophosphorylation of the catalytic subunit. J. Biol. Chem. 271, 8936-8941
77. Convery, E., Shin, E. K., Ding, Q., Wang, W., Douglas, P., Davis, L. S., Nickoloff, J. A., Lees-Miller, S. P. and Meek, K. (2005) Inhibition of homologous recombination by variants of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). Proc. Natl. Acad. Sci. U.S.A. 102, 1345-1350
78. Allen, C., Halbrook, J. and Nickoloff, J. A. (2003) Interactive competition between homologous recombination and non-homologous end joining. Mol. Cancer Res. 1, 913-920
79. Block, W. D., Yu, Y., Merkle, D., Gifford, J. L., Ding, Q., Meek, K. and Lees-Miller, S. P. (2004) Autophosphorylation-dependent remodeling of the DNA-dependent protein kinase catalytic subunit regulates ligation of DNA ends. Nucleic Acids Res. 32, 4351-4357
80. Douglas, P., Cui, X., Block, W. D., Yu, Y., Gupta, S., Ding, Q., Ye, R., Morrice, N., Lees-Miller, S. P. and Meek, K. (2007) 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. 27, 1581-1591
81. Cui, X., Yu, Y., Gupta, S., Cho, Y. M., Lees-Miller, S. P. and Meek, K. (2005) Autophosphorylation of DNA-dependent protein kinase regulates DNA end processing and may also alter double-strand break repair pathway choice. Mol. Cell. Biol. 25, 10842-10852
82. Budman, J. and Chu, G. (2005) Processing of DNA for nonhomologous end-joining by cell-free extract. EMBO J. 24, 849-860
83. Ma, Y., Pannicke, U., Schwarz, K. and Lieber, M. R. (2002) Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108, 781-794
84. Ma, Y., Schwarz, K. and Lieber, M. R. (2005) The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA Repair 4, 845-851
85. Povirk, L. F., Zhou, T., Zhou, R., Cowan, M. J. and Yannone, S. M. (2007) Processing of 3′-phosphoglycolate-terminated DNA double strand breaks by Artemis nuclease. J. Biol. Chem. 282, 3547-3558
86. Callebaut, I., Moshous, D., Mornon, J. P. and de Villartay, J. P. (2002) Metallo-β-lactamase fold within nucleic acids processing enzymes: the β-CASP family. Nucleic Acids Res. 30, 3592-3601
87. Rooney, S., Sekiguchi, J., Zhu, C., Cheng, H. L., Manis, J., Whitlow, S., DeVido, J., Foy, D., Chaudhuri, J., Lombard, D. and Alt, F. W. (2002) Leaky SCID phenotype associated with defective V(D)J coding end processing in artemis-deficient mice. Mol. Cell 10, 1379-1390
88. Moshous, D., Callebaut, I., de Chasseval, R., Corneo, B., Cavazzana-Calvo, M., Le Deist, F., Tezcan, I., Sanal, O., Bertrand, Y., Philippe, N. et al. (2001) 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
89. Soubeyrand, S., Pope, L., De Chasseval, R., Gosselin, D., Dong, F., de Villartay, J. P. and Hache, R. J. (2006) Artemis phosphorylated by DNA-dependent protein kinase associates preferentially with discrete regions of chromatin. J. Mol. Biol. 358, 1200-1211
90. Poinsignon, C., de Chasseval, R., Soubeyrand, S., Moshous, D., Fischer, A., Hache, R. J. and de Villartay, J. P. (2004) Phosphorylation of Artemis following irradiation-induced DNA damage. Eur. J. Immunol. 34, 3146-3155
91. Wang, J., Pluth, J. M., Cooper, P. K., Cowan, M. J., Chen, D. J. and Yannone, S. M. (2005) Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. DNA Repair 4, 556-570
92. Chen, L., Morio, T., Minegishi, Y., Nakada, S., Nagasawa, M., Komatsu, K., Chessa, L., Villa, A., Lecis, D., Delia, D. and Mizutani, S. (2005) Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. Cancer Sci. 96, 134-141
93. Zhang, X., Succi, J., Feng, Z., Prithivirajsingh, S., Story, M. D. and Legerski, R. J. (2004) Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. Mol. Cell. Biol. 24, 9207-9220
94. Geng, L., Zhang, X., Zheng, S. and Legerski, R. J. (2007) Artemis links ATM to G2/M checkpoint recovery via regulation of Cdk1-cyclin B. Mol. Cell. Biol. 27, 2625-2635
95. Niewolik, D., Pannicke, U., Lu, H., Ma, Y., Wang, L. C., Kulesza, P., Zandi, E., Lieber, M. R. and Schwarz, K. (2006) DNA-PKcs dependence of Artemis endonucleolytic activity, differences between hairpins and 5′ or 3′ overhangs. J. Biol. Chem. 281, 33900-33909
96. Yannone, S. M., Khan, I. S., Zhou, R. Z., Zhou, T., Valerie, K. and Povirk, L. F. (2008) Coordinate 5′ and 3′ endonucleolytic trimming of terminally blocked blunt DNA double-strand break ends by Artemis nuclease and DNA-dependent protein kinase. Nucleic Acids Res. 36, 3354-3365
97. Drouet, J., Frit, P., Delteil, C., de Villartay, J. P., Salles, B. and Calsou, P. (2006) Interplay between Ku, Artemis, and the DNA-dependent protein kinase catalytic subunit at DNA ends. J. Biol. Chem. 281, 27784-27793
98. Riballo, E., Kuhne, M., Rief, N., Doherty, A., Smith, G. C., Recio, M. J., Reis, C., Dahm, K., Fricke, A., Krempler, A. et al. (2004) A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to γ-H2AX foci. Mol. Cell 16, 715-724
99. Reference deleted
100. Jeggo, P. A. and Lobrich, M. (2005) Artemis links ATM to double strand break rejoining. Cell Cycle 4, 359-362
101. Nick McElhinny, S. A. and Ramsden, D. A. (2004) Sibling rivalry: competition between Pol X family members in V(D)J recombination and general double strand break repair. Immunol. Rev. 200, 156-164
102. Mueller, G. A., Moon, A. F., Derose, E. F., Havener, J. M., Ramsden, D. A., Pedersen, L. C. and London, R. E. (2008) A comparison of BRCT domains involved in nonhomologous end-joining: introducing the solution structure of the BRCT domain of polymerase γ. DNA Repair 7, 1340-1351
103. Moon, A. F., Garcia-Diaz, M., Batra, V. K., Beard, W. A., Bebenek, K., Kunkel, T. A., Wilson, S. H. and Pedersen, L. C. (2007) The X family portrait: structural insights into biological functions of X family polymerases. DNA Repair 6, 1709-1725
104. Nick McElhinny, S. A., Havener, J. M., Garcia-Diaz, M., Juarez, R., Bebenek, K., Kee, B. L., Blanco, L., Kunkel, T. A. and Ramsden, D. A. (2005) A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. Mol. Cell 19, 357-366
105. Paull, T. T. (2005) Saving the ends for last: the role of pol μ in DNA end joining. Mol. Cell 19, 294-296
106. Davis, B. J., Havener, J. M. and Ramsden, D. A. (2008) End-bridging is required for pol μ to efficiently promote repair of noncomplementary ends by nonhomologous end joining. Nucleic Acids Res. 36, 3085-3094
107. Bertocci, B., De Smet, A., Weill, J. C. and Reynaud, C. A. (2006) Nonoverlapping functions of DNA polymerases μ, lambda, and terminal deoxynucleotidyltransferase during immunoglobulin V(D)J recombination in vivo. Immunity 25, 31-41
108. Bernstein, N. K., Karimi-Busheri, F., Rasouli-Nia, A., Mani, R., Dianov, G., Glover, J. N. and Weinfeld, M. (2008) Polynucleotide kinase as a potential target for enhancing cytotoxicity by ionizing radiation and topoisomerase I inhibitors. Anticancer Agents Med. Chem. 8, 358-367
109. Koch, C. A., Agyei, R., Galicia, S., Metalnikov, P., O'Donnell, P., Starostine, A., Weinfeld, M. and Durocher, D. (2004) Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV. EMBO J. 23, 3874-3885
110. Chappell, C., Hanakahi, L. A., Karimi-Busheri, F., Weinfeld, M. and West, S. C. (2002) Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining. EMBO J. 21, 2827-2832
111. Rasouli-Nia, A., Karimi-Busheri, F. and Weinfeld, M. (2004) Stable down-regulation of human polynucleotide kinase enhances spontaneous mutation frequency and sensitizes cells to genotoxic agents. Proc. Natl. Acad. Sci. U.S.A. 101, 6905-6910
112. Karimi-Busheri, F., Rasouli-Nia, A., Allalunis-Turner, J. and Weinfeld, M. (2007) Human polynucleotide kinase participates in repair of DNA double-strand breaks by nonhomologous end joining but not homologous recombination. Cancer Res. 67, 6619-6625
113. Iles, N., Rulten, S., El-Khamisy, S. F. and Caldecott, K. W. (2007) APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal DNA strand breaks. Mol. Cell. Biol. 27, 3793-3803
114. Macrae, C. J., McCulloch, R. D., Ylanko, J., Durocher, D. and Koch, C. A. (2008) APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation. DNA Repair 7, 292-302
115. Ahel, I., Ahel, D., Matsusaka, T., Clark, A. J., Pines, J., Boulton, S. J. and West, S. C. (2008) Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature 451, 81-85
116. Bekker-Jensen, S., Fugger, K., Danielsen, J. R., Gromova, I., Sehested, M., Celis, J., Bartek, J., Lukas, J. and Mailand, N. (2007) Human Xip1 (C2orf13) is a novel regulator of cellular responses to DNA strand breaks. J. Biol. Chem. 282, 19638-19643
117. Kanno, S., Kuzuoka, H., Sasao, S., Hong, Z., Lan, L., Nakajima, S. and Yasui, A. (2007) A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses. EMBO J. 26, 2094-2103
118. Brosh, Jr, R. M. and Bohr, V. A. (2007) Human premature aging, DNA repair and RecQ helicases. Nucleic Acids Res. 35, 7527-7544
119. Li, B. and Comai, L. (2001) Requirements for the nucleolytic processing of DNA ends by the Werner syndrome protein-Ku70/80 complex. J. Biol. Chem. 276, 9896-9902
120. Cooper, M. P., Machwe, A., Orren, D. K., Brosh, R. M., Ramsden, D. and Bohr, V. A. (2000) Ku complex interacts with and stimulates the Werner protein. Genes Dev. 14, 907-912
121. Karmakar, P., Snowden, C. M., Ramsden, D. A. and Bohr, V. A. (2002) 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
122. Karmakar, P., Piotrowski, J., Brosh, Jr, R. M., Sommers, J. A., Lees-Miller, S. P., Cheng, W. H., Snowden, C. M., Ramsden, D. A. and Bohr, V. A. (2002) 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
123. Kusumoto, R., Dawut, L., Marchetti, C., Wan Lee, J., Vindigni, A., Ramsden, D. and Bohr, V. A. (2008) Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing. Biochemistry 47, 7548-7556
124. Zhou, T., Lee, J. W., Tatavarthi, H., Lupski, J. R., Valerie, K. and Povirk, L. F. (2005) Deficiency in 3′-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Nucleic Acids Res. 33, 289-297
125. Katyal, S., el-Khamisy, S. F., Russell, H. R., Li, Y., Ju, L., Caldecott, K. W. and McKinnon, P. J. (2007) TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. EMBO J. 26, 4720-4731
126. Dudasova, Z., Dudas, A. and Chovanec, M. (2004) Non-homologous end-joining factors of Saccharomyces cerevisiae. FEMS Microbiol. Rev. 28, 581-601
127. Di Virgilio, M. and Gautier, J. (2005) Repair of double-strand breaks by nonhomologous end joining in the absence of Mre11. J. Cell Biol. 171, 765-771
128. Lieber, M. R., Lu, H., Gu, J. and Schwarz, K. (2008) Flexibility in the order of action and in the enzymology of the nuclease, polymerases, and ligase of vertebrate non-homologous DNA end joining: relevance to cancer, aging, and the immune system. Cell Res. 18, 125-133
129. Lieber, M. R. (2008) The mechanism of human nonhomologous DNA end joining. J. Biol. Chem. 283, 1-5
130. Critchlow, S. E., Bowater, R. P. and Jackson, S. P. (1997) Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Curr. Biol. 7, 588-598
131. Li, Z., Otevrel, T., Gao, Y., Cheng, H. L., Seed, B., Stamato, T. D., Taccioli, G. E. and Alt, F. W. (1995) The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination. Cell 83, 1079-1089
132. Junop, M. S., Modesti, M., Guarne, A., Ghirlando, R., Gellert, M. and Yang, W. (2000) Crystal structure of the Xrcc4 DNA repair protein and implications for end joining. EMBO J. 19, 5962-5970
133. Leber, R., Wise, T. W., Mizuta, R. and Meek, K. (1998) The XRCC4 gene product is a target for and interacts with the DNA-dependent protein kinase. J. Biol. Chem. 273, 1794-1801
134. Sibanda, B. L., Critchlow, S. E., Begun, J., Pei, X. Y., Jackson, S. P., Blundell, T. L. and Pellegrini, L. (2001) Crystal structure of an Xrcc4-DNA ligase IV complex. Nat. Struct. Biol. 8, 1015-1019
135. Modesti, M., Junop, M. S., Ghirlando, R., van de Rakt, M., Gellert, M., Yang, W. and Kanaar, R. (2003) Tetramerization and DNA ligase IV interaction of the DNA double-strand break repair protein XRCC4 are mutually exclusive. J. Mol. Biol. 334, 215-228
136. Grawunder, U., Zimmer, D. and Leiber, M. R. (1998) DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains. Curr. Biol. 8, 873-876
137. Grawunder, U., Wilm, M., Wu, X., Kulesza, P., Wilson, T. E., Mann, M. and Lieber, M. R. (1997) Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature 388, 492-495
138. Gu, J., Lu, H., Tippin, B., Shimazaki, N., Goodman, M. F. and Lieber, M. R. (2007) XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps. EMBO J. 26, 1010-1023
139. Hsu, H. L., Yannone, S. M. and Chen, D. J. (2002) Defining interactions between DNA-PK and ligase IV/XRCC4. DNA Repair 1, 225-235
140. Ahnesorg, P., Smith, P. and Jackson, S. P. (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124, 301-313
141. Buck, D., Malivert, L., de Chasseval, R., Barraud, A., Fondaneche, M. C., Sanal, O., Plebani, A., Stephan, J. L., Hufnagel, M., le Deist, F. et al. (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124, 287-299
142. Sekiguchi, J. M. and Ferguson, D. O. (2006) DNA double-strand break repair: a relentless hunt uncovers new prey. Cell 124, 260-262
143. Modesti, M., Hesse, J. E. and Gellert, M. (1999) DNA binding of Xrcc4 protein is associated with V(D)J recombination but not with stimulation of DNA ligase IV activity. EMBO J. 18, 2008-2018
144. Drouet, J., Delteil, C., Lefrancois, J., Concannon, P., Salles, B. and Calsou, P. (2005) DNA-dependent protein kinase and XRCC4-DNA ligase IV mobilization in the cell in response to DNA double strand breaks. J. Biol. Chem. 280, 7060-7069
145. Matsumoto, Y., Suzuki, N., Namba, N., Umeda, N., Ma, X. J., Morita, A., Tomita, M., Enomoto, A., Serizawa, S., Hirano, K. et al. (2000) Cleavage and phosphorylation of XRCC4 protein induced by X-irradiation. FEBS Lett. 478, 67-71
146. Chen, L., Trujillo, K., Sung, P. and Tomkinson, A. E. (2000) Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. J. Biol. Chem. 275, 26196-26205
147. Lee, K. J., Jovanovic, M., Udayakumar, D., Bladen, C. L. and Dynan, W. S. (2004) Identification of DNA-PKcs phosphorylation sites in XRCC4 and effects of mutations at these sites on DNA end joining in a cell-free system. DNA Repair 3, 267-276
148. Yurchenko, V., Xue, Z. and Sadofsky, M. J. (2006) SUMO modification of human XRCC4 regulates its localization and function in DNA double-strand break repair. Mol. Cell. Biol. 26, 1786-1794
149. Li, Y., Chirgadze, D. Y., Bolanos-Garcia, V. M., Sibanda, B. L., Davies, O. R., Ahnesorg, P., Jackson, S. P. and Blundell, T. L. (2007) Crystal structure of human XLF/Cernunnos reveals unexpected differences from XRCC4 with implications for NHEJ. EMBO J. 27, 290-300
150. Andres, S. N., Modesti, M., Tsai, C. J., Chu, G. and Junop, M. S. (2007) Crystal structure of human XLF: a twist in nonhomologous DNA end-joining. Mol. Cell 28, 1093-1101
151. Lu, H., Pannicke, U., Schwarz, K. and Lieber, M. R. (2007) Length-dependent binding of human XLF to DNA and stimulation of XRCC4.DNA ligase IV activity. J. Biol. Chem. 282, 11155-11162
152. Tsai, C. J., Kim, S. A. and Chu, G. (2007) Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends. Proc. Natl. Acad. Sci. U.S.A. 104, 7851-7856
153. Hentges, P., Ahnesorg, P., Pitcher, R. S., Bruce, C. K., Kysela, B., Green, A. J., Bianchi, J., Wilson, T. E., Jackson, S. P. and Doherty, A. J. (2006) Evolutionary and functional conservation of the DNA non-homologous end-joining protein, XLF/Cernunnos. J. Biol. Chem. 281, 37517-37526
154. Gu, J., Lu, H., Tsai, A. G., Schwarz, K. and Lieber, M. R. (2007) Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence. Nucleic Acids Res. 35, 5755-5762
155. Williams, E. S., Stap, J., Essers, J., Ponnaiya, B., Luijsterburg, M. S., Krawczyk, P. M., Ullrich, R. L., Aten, J. A. and Bailey, S. M. (2007) DNA double-strand breaks are not sufficient to initiate recruitment of TRF2. Nat. Genet. 39, 696-698
156. Bekker-Jensen, S., Lukas, C., Kitagawa, R., Melander, F., Kastan, M. B., Bartek, J. and Lukas, J. (2006) Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. J. Cell Biol. 173, 195-206
157. Berkovich, E., Monnat, Jr, R. J. and Kastan, M. B. (2007) Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat. Cell Biol. 9, 683-690
158. Rodrigue, A., Lafrance, M., Gauthier, M. C., McDonald, D., Hendzel, M., West, S. C., Jasin, M. and Masson, J. Y. (2006) Interplay between human DNA repair proteins at a unique double-strand break in vivo. EMBO J. 25, 222-231
159. Barlow, J. H., Lisby, M. and Rothstein, R. (2008) Differential regulation of the cellular response to DNA double-strand breaks in G1. Mol. Cell 30, 73-85
160. Postow, L., Ghenoiu, C., Woo, E. M., Krutchinsky, A. N., Chait, B. T. and Funabiki, H. (2008) Ku80 removal from DNA through double strand break-induced ubiquitylation. J. Cell Biol. 182, 467-479
161. Dudley, D. D., Chaudhuri, J., Bassing, C. H. and Alt, F. W. (2005) Mechanism and control of V(D)J recombination versus class switch recombination: similarities and differences. Adv. Immunol. 86, 43-112
162. Boskovic, J., Rivera-Calzada, A., Maman, J. D., Chacon, P., Willison, K. R., Pearl, L. H. and Llorca, O. (2003) Visualization of DNA-induced conformational changes in the DNA repair kinase DNA-PKcs. EMBO J. 22, 5875-5882
163. Williams, D. R., Lee, K. J., Shi, J., Chen, D. J. and Stewart, P. L. (2008) Cryo-EM structure of the DNA-dependent protein kinase catalytic subunit at subnanometer resolution reveals α helices and insight into DNA binding. Structure 16, 468-477
164. Rivera-Calzada, A., Maman, J. D., Spagnolo, L., Pearl, L. H. and Llorca, O. (2005) Three-dimensional structure and regulation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Structure 13, 243-255
165. Kurz, E. U. and Lees-Miller, S. P. (2004) DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair 3, 889-900
166. Shiloh, Y. (2006) The ATM-mediated DNA-damage response: taking shape. Trends Biochem. Sci. 31, 402-410
167. Lavin, M. F. and Kozlov, S. (2007) ATM activation and DNA damage response. Cell Cycle 6, 931-942
168. Stiff, T., O'Driscoll, M., Rief, N., Iwabuchi, K., Lobrich, M. and Jeggo, P. A. (2004) ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res. 64, 2390-2396
169. Stucki, M. and Jackson, S. P. (2006) γH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes. DNA Repair 5, 534-543
170. Bozulic, L., Surucu, B., Hynx, D. and Hemmings, B. A. (2008) PKBa/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol. Cell 30, 203-213
171. Collis, S. J., DeWeese, T. L., Jeggo, P. A. and Parker, A. R. (2005) The life and death of DNA-PK. Oncogene 24, 949-961
172. Pastwa, E. and Malinowski, M. (2007) Non-homologous DNA end joining in anticancer therapy. Curr. Cancer Drug Targets 7, 243-250
173. Whitehouse, C. J., Taylor, R. M., Thistlethwaite, A., Zhang, H., Karimi-Busheri, F., Lasko, D. D., Weinfeld, M. and Caldecott, K. W. (2001) XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 104, 107-117
174. Loizou, J. I., El-Khamisy, S. F., Zlatanou, A., Moore, D. J., Chan, D. W., Qin, J., Sarno, S., Meggio, F., Pinna, L. A. and Caldecott, K. W. (2004) The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks. Cell 117, 17-28
175. Levy, N., Martz, A., Bresson, A., Spenlehauer, C., de Murcia, G. and Menissier-de Murcia, J. (2006) XRCC1 is phosphorylated by DNA-dependent protein kinase in response to DNA damage. Nucleic Acids Res. 34, 32-41
176. Shrivastav, M., De Haro, L. P. and Nickoloff, J. A. (2008) Regulation of DNA double-strand break repair pathway choice. Cell Res. 18, 134-147
177. Xie, A., Hartlerode, A., Stucki, M., Odate, S., Puget, N., Kwok, A., Nagaraju, G., Yan, C., Alt, F. W., Chen, J. et al. (2007) Distinct roles of chromatin-associated proteins MDC1 and 53BP1 in mammalian double-strand break repair. Mol. Cell 28, 1045-1057
178. Takeda, S., Nakamura, K., Taniguchi, Y. and Paull, T. T. (2007) Ctp1/ CtIP and the MRN complex collaborate in the initial steps of homologous recombination. Mol. Cell 28, 351-352
179. Reference deleted
180. Koike, M. (2002) Dimerization, translocation and localization of Ku70 and Ku80 proteins. J. Radiat. Res. 43, 223-236
181. Koike, M., Awaji, T., Kataoka, M., Tsujimoto, G., Kartasova, T., Koike, A. and Shiomi, T. (1999) Differential subcellular localization of DNA-dependent protein kinase components Ku and DNA-PKcs during mitosis. J. Cell Sci. 112, 4031-4039
182. Garcia-Diaz, M., Bebenek, K., Gao, G., Pedersen, L. C., London, R. E. and Kunkel, T. A. (2005) Structure-function studies of DNA polymerase λ. DNA Repair 4, 1358-1367
183. Bernstein, N. K., Williams, R. S., Rakovszky, M. L., Cui, D., Green, R., Karimi-Busheri, F., Mani, R. S., Galicia, S., Koch, C. A., Cass, C. E. et al. (2005) The molecular architecture of the mammalian DNA repair enzyme, polynucleotide kinase. Mol. Cell 17, 657-670
184. Li, Y., Chirgadze, D. Y., Bolanos-Garcia, V. M., Sibanda, B. L., Davies, O. R., Ahnesorg, P., Jackson, S. P. and Blundell, T. L. (2008) Crystal structure of human XLF/Cernunnos reveals unexpected differences from XRCC4 with implications for NHEJ. EMBO J. 27, 290-300