About this Journal Submit a Manuscript Table of Contents
ISRN Molecular Biology
Volume 2012 (2012), Article ID 345805, 16 pages
http://dx.doi.org/10.5402/2012/345805
Review Article

Processing of Damaged DNA Ends for Double-Strand Break Repair in Mammalian Cells

Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA 23298, USA

Received 27 September 2012; Accepted 7 November 2012

Academic Editors: A. Goldar and M. Greenwood

Copyright © 2012 Lawrence F. Povirk. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. F. Hutchinson, “Chemical changes induced in DNA by ionizing radiation,” Progress in Nucleic Acid Research and Molecular Biology, vol. 32, pp. 115–154, 1985. View at Publisher · View at Google Scholar · View at Scopus
  2. P. C. Dedon and I. H. Goldberg, “Free-radical mechanisms involved in the formation of sequence-dependent bistranded DNA lesions by the antitumor antibiotics bleomycin, neocarzinostatin, and calicheamicin,” Chemical Research in Toxicology, vol. 5, no. 3, pp. 311–332, 1992. View at Scopus
  3. L. F. Povirk, “DNA damage and mutagenesis by radiomimetic DNA-cleaving agents: bleomycin, neocarzinostatin and other enediynes,” Mutation Research, vol. 355, no. 1-2, pp. 71–89, 1996. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Cadet, J. L. Ravanat, M. Tavernaporro, H. Menoni, and D. Angelov, “Oxidatively generated complex DNA damage: tandem and clustered lesions,” Cancer Letters, vol. 327, no. 1-2, pp. 5–15, 2012. View at Publisher · View at Google Scholar
  5. G. E. Iliakis, G. E. Pantelias, R. Okayasu, and W. F. Blakely, “Induction by H2O2 of DNA and interphase chromosome damage in plateau- phase Chinese hamster ovary cells,” Radiation Research, vol. 131, no. 2, pp. 192–203, 1992. View at Scopus
  6. O. Sordet, C. E. Redon, J. Guirouilh-Barbat et al., “Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks,” EMBO Reports, vol. 10, no. 8, pp. 887–893, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. K. Valerie and L. F. Povirk, “Regulation and mechanisms of mammalian double-strand break repair,” Oncogene, vol. 22, no. 37, pp. 5792–5812, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. R. C. Getts and T. D. Stamato, “Absence of a Ku-like DNA end binding activity in the xrs double-strand DNA repair-deficient mutant,” Journal of Biological Chemistry, vol. 269, no. 23, pp. 15981–15984, 1994. View at Scopus
  9. M. Jasin, “Genetic manipulation of genomes with rare-cutting endonucleases,” Trends in Genetics, vol. 12, no. 6, pp. 224–228, 1996. View at Publisher · View at Google Scholar · View at Scopus
  10. A. Shibata, S. Conrad, J. Birraux et al., “Factors determining DNA double-strand break repair pathway choice in G2 phase,” EMBO Journal, vol. 30, no. 6, pp. 1079–1092, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. P. C. Dedon, “The chemical toxicology of 2-deoxyribose oxidation in DNA,” Chemical Research in Toxicology, vol. 21, no. 1, pp. 206–219, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Isildar, M. N. Schuchmann, D. Schulte-Frohlinde, and C. Von Sonntag, “γ-Radiolysis of DNA in oxygenated aqueous solution: alterations at the sugar moiety,” International Journal of Radiation Biology, vol. 40, no. 4, pp. 347–354, 1981. View at Scopus
  13. S. Chen, J. C. Hannis, J. W. Flora et al., “Homogeneous preparations of 3′-phosphoglycolate-terminated oligodeoxynucleotides from bleomycin-treated DNA as verified by electrospray ionization fourier transform ion cyclotron resonance mass spectrometry,” Analytical Biochemistry, vol. 289, no. 2, pp. 274–280, 2001. View at Publisher · View at Google Scholar · View at Scopus
  14. J. Kim, Y. N. Weledji, and M. M. Greenberg, “Independent generation and characterization of a C2′-oxidized abasic site in chemically synthesized oligonucleotides,” Journal of Organic Chemistry, vol. 69, no. 18, pp. 6100–6104, 2004. View at Publisher · View at Google Scholar · View at Scopus
  15. L. S. Kappen, I. H. Goldberg, and J. M. Liesch, “Identification of thymidine-5′-aldehyde at DNA strand breaks induced by neocarzinostatin chromophore,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 3, pp. 744–748, 1982. View at Scopus
  16. W. D. Henner, L. O. Rodriguez, S. M. Hecht, and W. A. Haseltine, “gamma Ray induced deoxyribonucleic acid strand breaks. 3′ Glycolate termini,” Journal of Biological Chemistry, vol. 258, no. 2, pp. 711–713, 1983. View at Scopus
  17. B. Chen, X. Zhou, K. Taghizadeh, J. Chen, J. Stubbe, and P. C. Dedon, “GC/MS methods to quantify the 2-deoxypentos-4-ulose and 3′-phosphoglycolate pathways of 4′ oxidation of 2-deoxyribose in DNA: application to DNA damage produced by γ radiation and bleomycin,” Chemical Research in Toxicology, vol. 20, no. 11, pp. 1701–1708, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. S. A. Roberts, N. Strande, M. D. Burkhalter et al., “Ku is a 5′-dRP/AP lyase that excises nucleotide damage near broken ends,” Nature, vol. 464, no. 7292, pp. 1214–1217, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. Y. Ma, H. Lu, B. Tippin et al., “A biochemically defined system for mammalian nonhomologous DNA end joining,” Molecular Cell, vol. 16, no. 5, pp. 701–713, 2004. View at Publisher · View at Google Scholar · View at Scopus
  20. C. J. Tsai, S. A. Kim, and G. Chu, “Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 19, pp. 7851–7856, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. J. Guirouilh-Barbat, E. Rass, I. Plo, P. Bertrand, and B. S. Lopez, “Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 52, pp. 20902–20907, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. K. Bebenek, M. Garcia-Diaz, R. Z. Zhou, L. F. Povirk, and T. A. Kunkel, “Loop 1 modulates the fidelity of DNA polymerase λ,” Nucleic Acids Research, vol. 38, no. 16, Article ID gkq261, pp. 5419–5431, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. R. Z. Zhou, L. Blanco, M. Garcia-Diaz, K. Bebenek, T. A. Kunkel, and L. F. Povirk, “Tolerance for 8-oxoguanine but not thymine glycol in alignment-based gap filling of partially complementary double-strand break ends by DNA polymerase λ in human nuclear extracts,” Nucleic Acids Research, vol. 36, no. 9, pp. 2895–2905, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. R. Z. Zhou, K. Akopiants, and L. F. Povirk, “Patching and single-strand ligation in nonhomologous DNA end joining despite persistence of a closely opposed 3′-phosphoglycolate-terminated strand break,” Radiation Research, vol. 174, no. 3, pp. 274–279, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. H. Nikjoo, P. O'Neill, D. T. Goodhead, and M. Terrissol, “Computational modelling of low-energy electron-induced DNA damage by early physical and chemical events,” International Journal of Radiation Biology, vol. 71, no. 5, pp. 467–483, 1997. View at Publisher · View at Google Scholar · View at Scopus
  26. E. J. Hall and A. J. Giaccia, Radiobiology for the Radiologist, Wolters Kluwer / Lippincott, Williams & Wilkins, Philedelphia, Pa, USA, 7th edition, 2012.
  27. J. F. Ward, “DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability,” Progress in Nucleic Acid Research and Molecular Biology, vol. 35, pp. 95–125, 1988. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Nikjoo, P. O'Neill, W. E. Wilson, and D. T. Goodhead, “Computational approach for determining the spectrum of DNA damage induced by ionizing radiation,” Radiation Research, vol. 156, no. 5, pp. 577–583, 2001. View at Scopus
  29. V. A. Semenenko and R. D. Stewart, “A fast Monte Carlo algorithm to simulate the spectrum of DNA damages formed by ionizing radiation,” Radiation Research, vol. 161, no. 4, pp. 451–457, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. K. Magnander and K. Elmroth, “Biological consequences of formation and repair of complex DNA damage,” Cancer Letters, vol. 327, no. 1-2, pp. 90–96, 2012. View at Publisher · View at Google Scholar
  31. M. H. David-Cordonnier, S. Boiteux, and P. O'Neill, “Efficiency of excision of 8-oxo-guanine within DNA clustered damage by XRS5 nuclear extracts and purified human OGG1 protein,” Biochemistry, vol. 40, no. 39, pp. 11811–11818, 2001. View at Publisher · View at Google Scholar · View at Scopus
  32. J. L. Parsons, D. O. Zharkov, and G. L. Dianov, “NEIL1 excises 3′ end proximal oxidative DNA lesions resistant to cleavage by NTH1 and OGG1,” Nucleic Acids Research, vol. 33, no. 15, pp. 4849–4856, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. M. M. Ali, T. K. Hazra, D. Hong, and Y. W. Kow, “Action of human endonucleases III and VIII upon DNA-containing tandem dihydrouracil,” DNA Repair, vol. 4, no. 6, pp. 679–686, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. L. F. Povirk, Y. H. Han, and R. J. Steighner, “Structure of bleomycin-induced DNA double-strand breaks: predominance of blunt ends and single-base 5′ extensions,” Biochemistry, vol. 28, no. 14, pp. 5808–5814, 1989. View at Scopus
  35. L. Giloni, M. Takeshita, and F. Johnson, “Bleomycin-induced strand-scission of DNA. Mechanism of deoxyribose cleavage,” Journal of Biological Chemistry, vol. 256, no. 16, pp. 8608–8615, 1981. View at Scopus
  36. S. Linn, “DNA damage by iron and hydrogen peroxide in vitro and in vivo,” Drug Metabolism Reviews, vol. 30, no. 2, pp. 313–326, 1998. View at Scopus
  37. M. S. Cooke, M. D. Evans, M. Dizdaroglu, and J. Lunec, “Oxidative DNA damage: mechanisms, mutation, and disease,” The FASEB Journal, vol. 17, no. 10, pp. 1195–1214, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. E. S. Henle, Z. Han, N. Tang, P. Rai, Y. Luo, and S. Linn, “Sequence-specific DNA cleavage by Fe2+-mediated fenton reactions has possible biological implications,” Journal of Biological Chemistry, vol. 274, no. 2, pp. 962–971, 1999. View at Publisher · View at Google Scholar · View at Scopus
  39. C. R. A. Bertoncini and R. Meneghini, “DNA strand breaks produced by oxidative stress in mammalian cells exhibit 3′-phosphoglycolate termini,” Nucleic Acids Research, vol. 23, no. 15, pp. 2995–3002, 1995. View at Scopus
  40. P. L. Olive and P. J. Johnston, “DNA damage from oxidants: influence of lesion complexity and chromatin organization,” Oncology Research, vol. 9, no. 6-7, pp. 287–294, 1997. View at Scopus
  41. P. L. Olive, “The role of DNA single- and double-strand breaks in cell killing by ionizing radiation,” Radiation Research, vol. 150, supplement 5, pp. S42–S51, 1998. View at Scopus
  42. A. H. Corbett and N. Osheroff, “When good enzymes go bad: conversion of topoisomerase II to a cellular toxin by antineoplastic drugs,” Chemical Research in Toxicology, vol. 6, no. 5, pp. 585–597, 1993. View at Scopus
  43. Y. Pommier, P. Pourquier, Y. Fan, and D. Strumberg, “Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme,” Biochimica et Biophysica Acta, vol. 1400, no. 1–3, pp. 83–106, 1998. View at Publisher · View at Google Scholar · View at Scopus
  44. O. Sordet, A. J. Nakamura, C. E. Redon, and Y. Pommier, “DNA double-strand breaks and ATM activation by transcription-blocking DNA lesions,” Cell Cycle, vol. 9, no. 2, pp. 274–278, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. L. F. Liu, S. D. Desai, T. K. Li, Y. Mao, M. Sun, and S. P. Sim, “Mechanism of action of camptothecin,” Annals of the New York Academy of Sciences, vol. 922, pp. 1–10, 2000. View at Scopus
  46. P. D'Arpa and L. F. Liu, “Topoisomerase-targeting antitumor drugs,” Biochimica et Biophysica Acta, vol. 989, no. 2, pp. 163–177, 1989. View at Publisher · View at Google Scholar · View at Scopus
  47. Y. Mao, S. D. Desai, C. Y. Ting, J. Hwang, and L. F. Liu, “26 S proteasome-mediated degradation of topoisomerase II cleavable complexes,” Journal of Biological Chemistry, vol. 276, no. 44, pp. 40652–40658, 2001. View at Publisher · View at Google Scholar · View at Scopus
  48. S. D. Desai, H. Zhang, A. Rodriguez-Bauman et al., “Transcription-dependent degradation of topoisomerase I-DNA covalent complexes,” Molecular and Cellular Biology, vol. 23, no. 7, pp. 2341–2350, 2003. View at Publisher · View at Google Scholar · View at Scopus
  49. C. P. Lin, Y. Ban, Y. L. Lyu, S. D. Desai, and L. F. Liu, “A ubiquitin-proteasome pathway for the repair of topoisomerase I-DNA covalent complexes,” Journal of Biological Chemistry, vol. 283, no. 30, pp. 21074–21083, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. C. P. Lin, Y. Ban, Y. L. Lyu, and L. F. Liu, “Proteasome-dependent processing of topoisomerase I-DNA adducts into DNA double strand breaks at arrested replication forks,” Journal of Biological Chemistry, vol. 284, no. 41, pp. 28084–28092, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. J. San Filippo, P. Sung, and H. Klein, “Mechanism of eukaryotic homologous recombination,” Annual Review of Biochemistry, vol. 77, pp. 229–257, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. S. W. Yang, A. B. Burgin, B. N. Huizenga, C. A. Robertson, K. C. Yao, and H. A. Nash, “A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 21, pp. 11534–11539, 1996. View at Publisher · View at Google Scholar · View at Scopus
  53. J. J. Pouliot, K. C. Yao, C. A. Robertson, and H. A. Nash, “Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes,” Science, vol. 286, no. 5439, pp. 552–555, 1999. View at Publisher · View at Google Scholar · View at Scopus
  54. H. Interthal, J. J. Pouliot, and J. J. Champoux, “The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 21, pp. 12009–12014, 2001. View at Publisher · View at Google Scholar · View at Scopus
  55. K. V. Inamdar, J. J. Pouliot, T. Zhou, S. P. Lees-Miller, A. Rasouli-Nia, and L. F. Povirk, “Conversion of phosphoglycolate to phosphate termini on 3′ overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1,” Journal of Biological Chemistry, vol. 277, no. 30, pp. 27162–27168, 2002. View at Publisher · View at Google Scholar · View at Scopus
  56. H. Interthal, H. J. Chen, and J. J. Champoux, “Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages,” Journal of Biological Chemistry, vol. 280, no. 43, pp. 36518–36528, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. D. R. Davies, H. Interthal, J. J. Champoux, and W. G. J. Hol, “The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1,” Structure, vol. 10, no. 2, pp. 237–248, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. A. C. Raymond, B. L. Staker, and A. B. Burgin, “Substrate specificity of tyrosyl-DNA phosphodiesterase I (Tdp1),” Journal of Biological Chemistry, vol. 280, no. 23, pp. 22029–22035, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. T. Zhou, K. Akopiants, S. Mohapatra et al., “Tyrosyl-DNA phosphodiesterase and the repair of 3′-phosphoglycolate-terminated DNA double-strand breaks,” DNA Repair, vol. 8, no. 8, pp. 901–911, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. H. Takashima, C. F. Boerkoel, J. John et al., “Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy,” Nature Genetics, vol. 32, no. 2, pp. 267–272, 2002. View at Publisher · View at Google Scholar · View at Scopus
  61. H. Interthal, H. J. Chen, T. E. Kehl-Fie, J. Zotzmann, J. B. Leppard, and J. J. Champoux, “SCAN1 mutant Tdp1 accumulates the enzyme-DNA intermediate and causes camptothecin hypersensitivity,” EMBO Journal, vol. 24, no. 12, pp. 2224–2233, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. R. Hirano, H. Interthal, C. Huang et al., “Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?” EMBO Journal, vol. 26, no. 22, pp. 4732–4743, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. S. Katyal, S. F. El-Khamisy, H. R. Russell et al., “TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo,” EMBO Journal, vol. 26, no. 22, pp. 4720–4731, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. A. J. Hawkins, M. A. Subler, K. Akopiants et al., “In vitro complementation of Tdp1 deficiency indicates a stabilized enzyme-DNA adduct from tyrosyl but not glycolate lesions as a consequence of the SCAN1 mutation,” DNA Repair, vol. 8, no. 5, pp. 654–663, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. J. Murai, S. Y. Huang, B. B. Das, T. S. Dexheimer, S. Takeda, and Y. Pommier, “Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs DNA damage induced by topoisomerases I and II and base alkylation in vertebrate cells,” Journal of Biological Chemistry, vol. 287, no. 16, pp. 12848–12857, 2012.
  66. S. F. El-Khamisy, G. M. Saifi, M. Weinfeld et al., “Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1,” Nature, vol. 434, no. 7029, pp. 108–113, 2005. View at Publisher · View at Google Scholar · View at Scopus
  67. S. F. El-Khamisy, E. Hartsuiker, and K. W. Caldecott, “TDP1 facilitates repair of ionizing radiation-induced DNA single-strand breaks,” DNA Repair, vol. 6, no. 10, pp. 1485–1495, 2007. View at Publisher · View at Google Scholar · View at Scopus
  68. Z. H. Miao, K. Agama, O. Sordet, L. Povirk, K. W. Kohn, and Y. Pommier, “Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes,” DNA Repair, vol. 5, no. 12, pp. 1489–1494, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. T. Zhou, J. W. Lee, H. Tatavarthi, J. R. Lupski, K. Valerie, and L. F. Povirk, “Deficiency in 3′-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1),” Nucleic Acids Research, vol. 33, no. 1, pp. 289–297, 2005. View at Publisher · View at Google Scholar · View at Scopus
  70. P. C. Dedon, A. A. Salzberg, and J. Xu, “Exclusive production of bistranded DNA damage by calicheamicin,” Biochemistry, vol. 32, no. 14, pp. 3617–3622, 1993. View at Scopus
  71. F. C. Ledesma, S. F. El Khamisy, M. C. Zuma, K. Osborn, and K. W. Caldecott, “A human 5′-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage,” Nature, vol. 461, no. 7264, pp. 674–678, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. K. C. Nitiss, M. Malik, X. He, S. W. White, and J. L. Nitiss, “Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 24, pp. 8953–8958, 2006. View at Publisher · View at Google Scholar · View at Scopus
  73. H. U. Barthelmes, M. Habermeyer, M. O. Christensen et al., “TDP1 overexpression in human cells counteracts DNA damage mediated by topoisomerases I and II,” Journal of Biological Chemistry, vol. 279, no. 53, pp. 55618–55625, 2004. View at Publisher · View at Google Scholar · View at Scopus
  74. Z. Zeng, F. Cortés-Ledesma, S. F. El Khamisy, and K. W. Caldecott, “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,” Journal of Biological Chemistry, vol. 286, no. 1, pp. 403–409, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. Z. Zeng, A. Sharma, L. Ju et al., “TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1,” Nucleic Acids Research, vol. 40, no. 17, pp. 8371–8380, 2012. View at Publisher · View at Google Scholar
  76. A. A. Sartori, C. Lukas, J. Coates et al., “Human CtIP promotes DNA end resection,” Nature, vol. 450, no. 7169, pp. 509–514, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. M. H. Yun and K. Hiom, “CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle,” Nature, vol. 459, no. 7245, pp. 460–463, 2009. View at Publisher · View at Google Scholar · View at Scopus
  78. J. Buis, T. Stoneham, E. Spehalski, and D. O. Ferguson, “Mre11 regulates CtIP-dependent double-strand break repair by interaction with CDK2,” Nature Structural & Molecular Biology, vol. 19, no. 2, pp. 246–252, 2012.
  79. B. M. Lengsfeld, A. J. Rattray, V. Bhaskara, R. Ghirlando, and T. T. Paull, “Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex,” Molecular Cell, vol. 28, no. 4, pp. 638–651, 2007. View at Publisher · View at Google Scholar · View at Scopus
  80. E. P. Mimitou and L. S. Symington, “DNA end resection: many nucleases make light work,” DNA Repair, vol. 8, no. 9, pp. 983–995, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. E. P. Mimitou and L. S. Symington, “Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing,” Nature, vol. 455, no. 7214, pp. 770–774, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. M. J. Neale, J. Pan, and S. Keeney, “Endonucleolytic processing of covalent protein-linked DNA double-strand breaks,” Nature, vol. 436, no. 7053, pp. 1053–1057, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. V. Quennet, A. Beucher, O. Barton, S. Takeda, and M. Löbrich, “CtIP and MRN promote non-homologous end-joining of etoposide-induced DNA double-strand breaks in G1,” Nucleic Acids Research, vol. 39, no. 6, pp. 2144–2152, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. P. L. Chen, F. Liu, S. Cai et al., “Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency,” Molecular and Cellular Biology, vol. 25, no. 9, pp. 3535–3542, 2005. View at Publisher · View at Google Scholar · View at Scopus
  85. K. Nakamura, T. Kogame, H. Oshiumi et al., “Collaborative action of Brca1 and CtIP in elimination of covalent modifications from double-strand breaks to facilitate subsequent break repair,” PLoS Genetics, vol. 6, no. 1, Article ID e1000828, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. F. Karimi-Busheri, G. Daly, P. Robins et al., “Molecular characterization of a human DNA kinase,” Journal of Biological Chemistry, vol. 274, no. 34, pp. 24187–24194, 1999. View at Publisher · View at Google Scholar · View at Scopus
  87. A. Jilani, D. Ramotar, C. Slack et al., “Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3′-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage,” Journal of Biological Chemistry, vol. 274, no. 34, pp. 24176–24186, 1999. View at Publisher · View at Google Scholar · View at Scopus
  88. C. J. Whitehouse, R. M. Taylor, A. Thistlethwaite et al., “XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair,” Cell, vol. 104, no. 1, pp. 107–117, 2001. View at Publisher · View at Google Scholar · View at Scopus
  89. C. A. Koch, R. Agyei, S. Galicia et al., “Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV,” EMBO Journal, vol. 23, no. 19, pp. 3874–3885, 2004. View at Publisher · View at Google Scholar · View at Scopus
  90. J. Della-Maria, M. L. Hegde, D. R. McNeill et al., “The interaction between polynucleotide kinase phosphatase and the DNA repair protein XRCC1 is critical for repair of DNA alkylation damage and stable association at DNA damage sites,” Journal of Biological Chemistry, vol. 287, no. 46, pp. 39233–39244, 2012. View at Publisher · View at Google Scholar
  91. A. Rasouli-Nia, F. Karimi-Busheri, and M. Weinfeld, “Stable down-regulation of human polynucleotide kinase enhances spontaneous mutation frequency and sensitizes cells to genotoxic agents,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 18, pp. 6905–6910, 2004. View at Publisher · View at Google Scholar · View at Scopus
  92. M. Z. Hadi and D. M. Wilson III, “Second human protein with homology to the Escherichia coli abasic endonuclease exonuclease III,” Environmental and Molecular Mutagenesis, vol. 36, no. 4, pp. 312–324, 2000.
  93. M. Z. Hadi, K. Ginalski, L. H. Nguyen, and D. M. Wilson, “Determinants in nuclease specificity of Ape1 and Ape2, human homologues of Escherichia coli exonuclease III,” Journal of Molecular Biology, vol. 316, no. 3, pp. 853–866, 2002. View at Publisher · View at Google Scholar · View at Scopus
  94. P. Burkovics, V. Szukacsov, I. Unk, and L. Haracska, “Human Ape2 protein has a 3′-5′ exonuclease activity that acts preferentially on mismatched base pairs,” Nucleic Acids Research, vol. 34, no. 9, pp. 2508–2515, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. D. Suh, D. M. Wilson, and L. F. Povirk, “3′-Phosphodiesterase activity of human apurinic/apyrimidinic endonuclease at DNA double-strand break ends,” Nucleic Acids Research, vol. 25, no. 12, pp. 2495–2500, 1997. View at Publisher · View at Google Scholar · View at Scopus
  96. S. Xanthoudakis, R. J. Smeyne, J. D. Wallace, and T. Curran, “The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 17, pp. 8919–8923, 1996. View at Publisher · View at Google Scholar · View at Scopus
  97. T. Izumi, D. B. Brown, C. V. Naidu et al., “Two essential but distinct functions of the mammalian abasic endonuclease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 16, pp. 5739–5743, 2005. View at Publisher · View at Google Scholar · View at Scopus
  98. H. Fung and B. Demple, “Distinct roles of Ape1 protein in the repair of DNA damage induced by ionizing radiation or bleomycin,” Journal of Biological Chemistry, vol. 286, no. 7, pp. 4968–4977, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. U. I. Chung, T. Igarashi, T. Nishishita et al., “The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium,” Journal of Biological Chemistry, vol. 271, no. 15, pp. 8593–8598, 1996. View at Publisher · View at Google Scholar · View at Scopus
  100. J. A. Harrigan, J. Fan, J. Momand, F. W. Perrino, V. A. Bohr, and D. M. Wilson, “WRN exonuclease activity is blocked by DNA termini harboring 3′ obstructive groups,” Mechanisms of Ageing and Development, vol. 128, no. 3, pp. 259–266, 2007. View at Publisher · View at Google Scholar · View at Scopus
  101. P. Burkovics, I. Hajdú, V. Szukacsov, I. Unk, and L. Haracska, “Role of PCNA-dependent stimulation of 3′-phosphodiesterase and 3′-5′ exonuclease activities of human Ape2 in repair of oxidative DNA damage,” Nucleic Acids Research, vol. 37, no. 13, pp. 4247–4255, 2009. View at Publisher · View at Google Scholar · View at Scopus
  102. D. Moshous, I. Callebaut, R. De Chasseval et al., “Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency,” Cell, vol. 105, no. 2, pp. 177–186, 2001. View at Publisher · View at Google Scholar · View at Scopus
  103. L. Li, D. Moshous, Y. Zhou et al., “A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans,” Journal of Immunology, vol. 168, no. 12, pp. 6323–6329, 2002. View at Scopus
  104. K. S. Pawelczak and J. J. Turchi, “Purification and characterization of exonuclease-free Artemis: implications for DNA-PK-dependent processing of DNA termini in NHEJ-catalyzed DSB repair,” DNA Repair, vol. 9, no. 6, pp. 670–677, 2010. View at Publisher · View at Google Scholar · View at Scopus
  105. Y. Ma, U. Pannicke, K. Schwarz, and M. R. Lieber, “Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination,” Cell, vol. 108, no. 6, pp. 781–794, 2002. View at Publisher · View at Google Scholar · View at Scopus
  106. L. F. Povirk, T. Zhou, R. Zhou, M. J. Cowan, and S. M. Yannone, “Processing of 3′-phosphoglycolate-terminated DNA double strand breaks by artemis nuclease,” Journal of Biological Chemistry, vol. 282, no. 6, pp. 3547–3558, 2007. View at Publisher · View at Google Scholar · View at Scopus
  107. S. M. Yannone, I. S. Khan, R. Z. Zhou, T. Zhou, K. Valerie, and L. F. Povirk, “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 Research, vol. 36, no. 10, pp. 3354–3365, 2008. View at Publisher · View at Google Scholar · View at Scopus
  108. S. Mohapatra, M. Kawahara, I. S. Khan, S. M. Yannone, and L. F. Povirk, “Restoration of G1 chemo/radioresistance and double-strand-break repair proficiency by wild-type but not endonuclease-deficient Artemis,” Nucleic Acids Research, vol. 39, no. 15, pp. 6500–6510, 2011. View at Publisher · View at Google Scholar
  109. A. A. Goodarzi, A. T. Noon, D. Deckbar et al., “ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin,” Molecular Cell, vol. 31, no. 2, pp. 167–177, 2008. View at Publisher · View at Google Scholar · View at Scopus
  110. E. Riballo, M. Kühne, N. Rief et al., “A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to γ-H2AX foci,” Molecular Cell, vol. 16, no. 5, pp. 715–724, 2004. View at Publisher · View at Google Scholar · View at Scopus
  111. A. T. Noon, A. Shibata, N. Rief et al., “53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair,” Nature Cell Biology, vol. 12, no. 2, pp. 177–184, 2010. View at Publisher · View at Google Scholar · View at Scopus
  112. P. Kanikarla-Marie, S. Ronald, and A. De Benedetti, “Nucleosome resection at a double-strand break during Non-Homologous Ends Joining in mammalian cells—implications from repressive chromatin organization and the role of ARTEMIS,” BMC Research Notes, vol. 4, article 13, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. A. Kurosawa, H. Koyama, S. Takayama et al., “The requirement of Artemis in double-strand break repair depends on the type of DNA damage,” DNA and Cell Biology, vol. 27, no. 1, pp. 55–61, 2008. View at Publisher · View at Google Scholar · View at Scopus
  114. J. Wang, J. M. Pluth, P. K. Cooper, M. J. Cowan, D. J. Chen, and S. M. Yannone, “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, vol. 4, no. 5, pp. 556–570, 2005. View at Publisher · View at Google Scholar · View at Scopus
  115. S. H. Lee, M. Oshige, S. T. Durant et al., “The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 50, pp. 18075–18080, 2005. View at Publisher · View at Google Scholar · View at Scopus
  116. B. D. Beck, S. S. Lee, E. Williamson, R. A. Hromas, and S. H. Lee, “Biochemical characterization of metnases endonuclease activity and its role in NHEJ repair,” Biochemistry, vol. 50, no. 20, pp. 4360–4370, 2011. View at Publisher · View at Google Scholar · View at Scopus
  117. S. Fnu, E. A. Williamson, L. P. De Haro et al., “Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 2, pp. 540–545, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. R. Hromas, J. Wray, S. H. Lee et al., “The human set and transposase domain protein Metnase interacts with DNA Ligase IV and enhances the efficiency and accuracy of non-homologous end-joining,” DNA Repair, vol. 7, no. 12, pp. 1927–1937, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. B. Demple, A. Johnson, and D. Fung, “Exonuclease III and endonuclease IV remove 3′ blocks from DNA synthesis primers in H2O2-damaged Escherichia coli,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 20, pp. 7731–7735, 1986. View at Scopus
  120. T. Lindahl, J. A. Gally, and G. M. Edelman, “Properties of deoxyribonuclease 3 from mammalian tissues,” Journal of Biological Chemistry, vol. 244, no. 18, pp. 5014–5019, 1969. View at Scopus
  121. K. V. Inamdar, Y. Yu, and L. F. Povirk, “Resistance of 3′-phosphoglycolate DNA ends to digestion by mammalian DNase III,” Radiation Research, vol. 157, no. 3, pp. 306–311, 2002. View at Scopus
  122. U. De Silva, S. Choudhury, S. L. Bailey, S. Harvey, F. W. Perrino, and T. Hollis, “The crystal structure of TREX1 explains the 3′ nucleotide specificity and reveals a polyproline II helix for protein partnering,” Journal of Biological Chemistry, vol. 282, no. 14, pp. 10537–10543, 2007. View at Publisher · View at Google Scholar · View at Scopus
  123. R. Kusumoto, L. Dawut, C. Marchetti et al., “Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing,” Biochemistry, vol. 47, no. 28, pp. 7548–7556, 2008. View at Publisher · View at Google Scholar · View at Scopus
  124. T. Bessho and A. Sancar, “Human DNA damage checkpoint protein hRAD9 is a 3′ to 5′ exonuclease,” Journal of Biological Chemistry, vol. 275, no. 11, pp. 7451–7454, 2000. View at Publisher · View at Google Scholar · View at Scopus
  125. K. M. Trujillo, S. S. F. Yuan, E. Y. H. P. Lee, and P. Sung, “Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95,” Journal of Biological Chemistry, vol. 273, no. 34, pp. 21447–21450, 1998. View at Publisher · View at Google Scholar · View at Scopus
  126. Y. Yan, S. Akhter, X. Zhang, and R. Legerski, “The multifunctional SNM1 gene family: not just nucleases,” Future Oncology, vol. 6, no. 6, pp. 1015–1029, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. B. I. Lee and D. M. Wilson, “The RAD2 domain of human exonuclease 1 exhibits 5′ to 3′ exonuclease and flap structure-specific endonuclease activities,” Journal of Biological Chemistry, vol. 274, no. 53, pp. 37763–37769, 1999. View at Publisher · View at Google Scholar · View at Scopus
  128. C. MacKay, A. C. Déclais, C. Lundin et al., “Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2,” Cell, vol. 142, no. 1, pp. 65–76, 2010. View at Publisher · View at Google Scholar · View at Scopus
  129. I. Ahel, U. Rass, S. F. El-Khamisy et al., “The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates,” Nature, vol. 443, no. 7112, pp. 713–716, 2006. View at Publisher · View at Google Scholar · View at Scopus
  130. S. Li, S. Kanno, R. Watanabe et al., “Polynucleotide kinase and aprataxin-like forkhead-associated protein (PALF) acts as both a single-stranded DNA endonuclease and a single-stranded DNA 3′ exonuclease and can participate in DNA end joining in a biochemical system,” Journal of Biological Chemistry, vol. 286, no. 42, pp. 36368–36377, 2011.
  131. X. Wu, T. E. Wilson, and M. R. Lieber, “A role for FEN-1 in nonhomologous DNA end joining: the order of strand annealing and nucleolytic processing events,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 4, pp. 1303–1308, 1999. View at Publisher · View at Google Scholar · View at Scopus
  132. J. R. Walker, R. A. Corpina, and J. Goldberg, “Structure of the Ku heterodimer bound to dna and its implications for double-strand break repair,” Nature, vol. 412, no. 6847, pp. 607–614, 2001. View at Publisher · View at Google Scholar · View at Scopus
  133. H. L. Hsu, S. M. Yannone, and D. J. Chen, “Defining interactions between DNA-PK and ligase IV/XRCC4,” DNA Repair, vol. 1, no. 3, pp. 225–235, 2002. View at Publisher · View at Google Scholar · View at Scopus
  134. D. A. Ramsden and M. Geliert, “Ku protein stimulates DNA end joining by mammalian DNA ligases: a direct role for Ku in repair of DNA double-strand breaks,” EMBO Journal, vol. 17, no. 2, pp. 609–614, 1998. View at Publisher · View at Google Scholar · View at Scopus
  135. N. Strande, S. A. Roberts, S. Oh, E. A. Hendrickson, and D. A. Ramsden, “Specificity of the dRP/AP lyase of Ku promotes nonhomologous end joining (NHEJ) fidelity at damaged ends,” Journal of Biological Chemistry, vol. 287, no. 17, pp. 13686–13693, 2012.
  136. M. R. Lieber, H. Lu, J. Gu, and K. Schwarz, “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 Research, vol. 18, no. 1, pp. 125–133, 2008. View at Publisher · View at Google Scholar · View at Scopus
  137. J. Gu, H. Lu, A. G. Tsai, K. Schwarz, and M. R. Lieber, “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 Research, vol. 35, no. 17, pp. 5755–5762, 2007. View at Publisher · View at Google Scholar · View at Scopus
  138. A. J. Picher, M. García-Díaz, K. Bebenek, L. C. Pedersen, T. A. Kunkel, and L. Blanco, “Promiscuous mismatch extension by human DNA polymerase lambda,” Nucleic Acids Research, vol. 34, no. 11, pp. 3259–3266, 2006. View at Scopus
  139. M. Garcia-Diaz, K. Bebenek, J. M. Krahn, L. C. Pedersen, and T. A. Kunkel, “Structural analysis of strand misalignment during DNA synthesis by a human DNA polymerase,” Cell, vol. 124, no. 2, pp. 331–342, 2006. View at Publisher · View at Google Scholar · View at Scopus
  140. K. Datta, S. Purkayastha, R. D. Neumann, E. Pastwa, and T. A. Winters, “Base damage immediately upstream from double-strand break ends is a more severe impediment to nonhomologous end joining than blocked 3′-termini,” Radiation Research, vol. 175, no. 1, pp. 97–112, 2011. View at Publisher · View at Google Scholar · View at Scopus