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DNA Repair

  • Kerstin Borgmann
  • Sabrina Köcher
  • Malte Kriegs
  • Wael Yassin Mansour
  • Ann Christin Parplys
  • Thorsten Rieckmann
  • Kai RothkammEmail author
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 198)

Abstract

Cellular chromosomal DNA is the principal target through which ionising radiation exerts it diverse biological effects. This chapter summarises the relevant DNA damage signalling and repair pathways used by normal and tumour cells in response to irradiation. Strategies for tumour radiosensitisation are reviewed which exploit tumour-specific DNA repair deficiencies or signalling pathway addictions, with a special focus on growth factor signalling, PARP, cancer stem cells, cell cycle checkpoints and DNA replication. This chapter concludes with a discussion of DNA repair-related candidate biomarkers of tumour response which are of crucial importance for implementing precision medicine in radiation oncology.

Keyword

Ionising radiation DNA damage response DNA strand breaks DNA double-strand break repair Molecular targeting Biomarkers 

References

  1. Ahmed SU, Carruthers R, Gilmour L, Yildirim S, Watts C, Chalmers AJ (2015) Selective inhibition of parallel DNA damage response pathways optimizes radiosensitization of glioblastoma stem-like cells. Cancer ResGoogle Scholar
  2. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988PubMedPubMedCentralCrossRefGoogle Scholar
  3. Andersen SL, Kuo HK, Savukoski D, Brodsky MH, Sekelsky J (2011) Three structure-selective endonucleases are essential in the absence of BLM helicase in Drosophila. PLoS Genet 7:e1002315PubMedPubMedCentralCrossRefGoogle Scholar
  4. Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, Fu KK, Milas L (2002) Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 62:7350–7356PubMedGoogle Scholar
  5. Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, El-Naggar AK et al (2014) Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol Official J Am Soc Clin Oncol 32:2940–2950CrossRefGoogle Scholar
  6. Audebert M, Salles B, 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 279:55117–55126PubMedCrossRefGoogle Scholar
  7. Azqueta A, Langie SA, Slyskova J, Collins AR (2013) Measurement of DNA base and nucleotide excision repair activities in mammalian cells and tissues using the comet assay–a methodological overview. DNA Repair 12:1007–1010PubMedCrossRefGoogle Scholar
  8. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRefGoogle Scholar
  9. Barber RC, Hickenbotham P, Hatch T, Kelly D, Topchiy N, Almeida GM, Jones GD, Johnson GE, Parry JM, Rothkamm K et al (2006) Radiation-induced transgenerational alterations in genome stability and DNA damage. Oncogene 25:7336–7342PubMedCrossRefGoogle Scholar
  10. Barnard S, Bouffler S, Rothkamm K (2013) The shape of the radiation dose response for DNA double-strand break induction and repair. Genome Integrity 4:1PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bartucci M, Svensson S, Romania P, Dattilo R, Patrizii M, Signore M, Navarra S, Lotti F, Biffoni M, Pilozzi E et al (2012) Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy. Cell Death Differ 19:768–778PubMedCrossRefGoogle Scholar
  12. Bauerschmidt C, Arrichiello C, Burdak-Rothkamm S, Woodcock M, Hill MA, Stevens DL, Rothkamm K (2010) Cohesin promotes the repair of ionizing radiation-induced DNA double-strand breaks in replicated chromatin. Nucleic Acids Res 38:477–487PubMedCrossRefGoogle Scholar
  13. Baumann M, Krause M, Hill R (2008) Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545–554PubMedCrossRefGoogle Scholar
  14. Bekker-Jensen S, Mailand N (2011) The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks. FEBS Lett 585:2914–2919PubMedCrossRefGoogle Scholar
  15. Benafif S, Hall M (2015) An update on PARP inhibitors for the treatment of cancer. OncoTargets Ther 8:519–528Google Scholar
  16. Bentley J, Diggle CP, Harnden P, Knowles MA, Kiltie AE (2004) DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining. Nucleic Acids Res 32:5249–5259PubMedPubMedCentralCrossRefGoogle Scholar
  17. Bjork-Eriksson T, West C, Karlsson E, Mercke C (2000) Tumor radiosensitivity (SF2) is a prognostic factor for local control in head and neck cancers. Int J Radiat Oncol Biol Phys 46:13–19PubMedCrossRefGoogle Scholar
  18. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Eng J Med 354:567–578CrossRefGoogle Scholar
  19. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28PubMedCrossRefGoogle Scholar
  20. Brenerman BM, Illuzzi JL, Wilson DM 3rd (2014) Base excision repair capacity in informing healthspan. Carcinogenesis 35:2643–2652PubMedPubMedCentralCrossRefGoogle Scholar
  21. Brown JS, Jackson SP (2015) Ubiquitylation, neddylation and the DNA damage response. Open Biol 5:150018PubMedPubMedCentralCrossRefGoogle Scholar
  22. Bryant HE, Helleday T (2004) Poly(ADP-ribose) polymerase inhibitors as potential chemotherapeutic agents. Biochem Soc Trans 32:959–961PubMedCrossRefGoogle Scholar
  23. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917PubMedCrossRefGoogle Scholar
  24. Busch CJ, Kriegs M, Laban S, Tribius S, Knecht R, Petersen C, Dikomey E, Rieckmann T (2013) HPV-positive HNSCC cell lines but not primary human fibroblasts are radiosensitized by the inhibition of Chk1. Radiother Oncol J Eur Soc Ther Radiol Oncol 108:495–499CrossRefGoogle Scholar
  25. Cai Z, Chen Z, Bailey KE, Scollard DA, Reilly RM, Vallis KA (2008) Relationship between induction of phosphorylated H2AX and survival in breast cancer cells exposed to 111In-DTPA-hEGF. J Nucl Med Official Pub Soc Nucl Med 49:1353–1361Google Scholar
  26. Caldecott KW (2014) DNA single-strand break repair. Exp Cell Res 329:2–8PubMedCrossRefGoogle Scholar
  27. Catz SD, Johnson JL (2003) BCL-2 in prostate cancer: a minireview. Apoptosis Int J Programmed Cell Death 8:29–37CrossRefGoogle Scholar
  28. Cheng L, Wu Q, Huang Z, Guryanova OA, Huang Q, Shou W, Rich JN, Bao S (2011) L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO J 30:800–813PubMedPubMedCentralCrossRefGoogle Scholar
  29. Cheng Y, Li F, Mladenov E, Iliakis G (2015) The yield of DNA double strand breaks determined after exclusion of those forming from heat-labile lesions predicts tumor cell radiosensitivity to killing. Radiother Oncol J Eur Soc Ther Radiol OncolGoogle Scholar
  30. Chua ML, Rothkamm K (2013) Biomarkers of radiation exposure: can they predict normal tissue radiosensitivity? Clin Oncol 25:610–616CrossRefGoogle Scholar
  31. Collins AR (2014) Measuring oxidative damage to DNA and its repair with the comet assay. Biochim Biophys Acta 1840:794–800PubMedCrossRefGoogle Scholar
  32. Crosbie JC, Anderson RL, Rothkamm K, Restall CM, Cann L, Ruwanpura S, Meachem S, Yagi N, Svalbe I, Lewis RA et al (2010) Tumor cell response to synchrotron microbeam radiation therapy differs markedly from cells in normal tissues. Int J Radiat Oncol Biol Phys 77:886–894PubMedCrossRefGoogle Scholar
  33. Czarny P, Pawlowska E, Bialkowska-Warzecha J, Kaarniranta K, Blasiak J (2015) Autophagy in DNA damage response. Int J Mol Sci 16:2641–2662PubMedPubMedCentralCrossRefGoogle Scholar
  34. Dahm-Daphi J, Dikomey E (1996) Rejoining of DNA double-strand breaks in X-irradiated CHO cells studied by constant- and graded-field gel electrophoresis. Int J Radiat Biol 69:615–621PubMedCrossRefGoogle Scholar
  35. Davis AJ, Chen DJ (2013) DNA double strand break repair via non-homologous end-joining. Transl Cancer Res 2:130–143PubMedPubMedCentralGoogle Scholar
  36. Desai A, Webb B, Gerson SL (2014) CD133+ cells contribute to radioresistance via altered regulation of DNA repair genes in human lung cancer cells. Radiother Oncol J Eur Soc Ther Radiol Oncol 110:538–545CrossRefGoogle Scholar
  37. Dillon MT, Good JS, Harrington KJ (2014) Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy. Clin Oncol 26:257–265CrossRefGoogle Scholar
  38. Dobbelstein M, Sorensen CS (2015) Exploiting replicative stress to treat cancer. Nat Rev Drug Discov 14:405–423PubMedCrossRefGoogle Scholar
  39. Dungey FA, Loser DA, Chalmers AJ (2008) Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. Int J Radiat Oncol Biol Phys 72:1188–1197PubMedCrossRefGoogle Scholar
  40. El-Awady RA, Dikomey E, Dahm-Daphi J (2003) Radiosensitivity of human tumour cells is correlated with the induction but not with the repair of DNA double-strand breaks. Br J Cancer 89:593–601PubMedPubMedCentralCrossRefGoogle Scholar
  41. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Eng J Med 361:123–134CrossRefGoogle Scholar
  42. Garrett MD, Collins I (2011) Anticancer therapy with checkpoint inhibitors: what, where and when? Trends Pharmacol Sci 32:308–316PubMedCrossRefGoogle Scholar
  43. Giralt J, Trigo J, Nuyts S, Ozsahin M, Skladowski K, Hatoum G, Daisne JF, Yunes Ancona AC, Cmelak A, Mesia R et al (2015) Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 16:221–232PubMedCrossRefGoogle Scholar
  44. Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Lobrich M, Jeggo PA (2008) ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell 31:167–177PubMedCrossRefGoogle Scholar
  45. Groth P, Orta ML, Elvers I, Majumder MM, Lagerqvist A, Helleday T (2012) Homologous recombination repairs secondary replication induced DNA double-strand breaks after ionizing radiation. Nucleic Acids Res 40:6585–6594PubMedPubMedCentralCrossRefGoogle Scholar
  46. Harari PM, Allen GW, Bonner JA (2007) Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol Official J Am Soc Clin Oncol 25:4057–4065CrossRefGoogle Scholar
  47. Helleday T, Lo J, van Gent DC, Engelward BP (2007) DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair 6:923–935PubMedCrossRefGoogle Scholar
  48. Huang F, Mazin AV (2014) A small molecule inhibitor of human RAD51 potentiates breast cancer cell killing by therapeutic agents in mouse xenografts. PLoS ONE 9:e100993PubMedPubMedCentralCrossRefGoogle Scholar
  49. Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461:1071–1078PubMedPubMedCentralCrossRefGoogle Scholar
  50. Jager U, Bocskor S, Le T, Mitterbauer G, Bolz I, Chott A, Kneba M, Mannhalter C, Nadel B (2000) Follicular lymphomas’ BCL-2/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation. Blood 95:3520–3529PubMedGoogle Scholar
  51. Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, Doerks T, Julien P, Roth A, Simonovic M et al (2009) STRING 8–a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res 37:D412–D416PubMedCrossRefGoogle Scholar
  52. Koi L, Bergmann R, Bruchner K, Pietzsch J, Pietzsch HJ, Krause M, Steinbach J, Zips D, Baumann M (2014) Radiolabeled anti-EGFR-antibody improves local tumor control after external beam radiotherapy and offers theragnostic potential. Radiother Oncol J Eur Soc Ther Radiol Oncol 110:362–369CrossRefGoogle Scholar
  53. Kotsantis P, Jones RM, Higgs MR, Petermann E (2015) Cancer therapy and replication stress: forks on the road to perdition. Adv Clin Chem 69:91–138PubMedCrossRefGoogle Scholar
  54. Kotter A, Cornils K, Borgmann K, Dahm-Daphi J, Petersen C, Dikomey E, Mansour WY (2014) Inhibition of PARP1-dependent end-joining contributes to Olaparib-mediated radiosensitization in tumor cells. Mol Oncol 8:1616–1625PubMedCrossRefGoogle Scholar
  55. Krause DS, Van Etten RA (2005) Tyrosine kinases as targets for cancer therapy. N Eng J Med 353:172–187CrossRefGoogle Scholar
  56. Kriegs M, Gurtner K, Can Y, Brammer I, Rieckmann T, Oertel R, Wysocki M, Dorniok F, Gal A, Grob TJ et al (2015) Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest. Radiother Oncol J Eur Soc Ther Radiol Oncol 115:120–127CrossRefGoogle Scholar
  57. Kriegs M, Kasten-Pisula U, Rieckmann T, Holst K, Saker J, Dahm-Daphi J, Dikomey E (2010) The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining. DNA Repair 9:889–897PubMedCrossRefGoogle Scholar
  58. Laban S, Steinmeister L, Gleißner L, Grob TJ, Grénman R, Petersen C, Gal A, Knecht R, Dikomey E, Kriegs M (2013) Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation. Radiother Oncol 109:286–292Google Scholar
  59. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648PubMedCrossRefGoogle Scholar
  60. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J (2009) Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol Official J Am Soc Clin Oncol 27:1992–1998CrossRefGoogle Scholar
  61. Lee SW, Cho KJ, Park JH, Kim SY, Nam SY, Lee BJ, Kim SB, Choi SH, Kim JH, Ahn SD et al (2005) Expressions of Ku70 and DNA-PKcs as prognostic indicators of local control in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 62:1451–1457PubMedCrossRefGoogle Scholar
  62. Lieber MR, Ma Y, Pannicke U, Schwarz K (2003) Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4:712–720PubMedCrossRefGoogle Scholar
  63. Lundholm L, Haag P, Zong D, Juntti T, Mork B, Lewensohn R, Viktorsson K (2013) Resistance to DNA-damaging treatment in non-small cell lung cancer tumor-initiating cells involves reduced DNA-PK/ATM activation and diminished cell cycle arrest. Cell Death Dis 4:e478PubMedPubMedCentralCrossRefGoogle Scholar
  64. Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21:283–296PubMedPubMedCentralCrossRefGoogle Scholar
  65. Mandal PK, Blanpain C, Rossi DJ (2011) DNA damage response in adult stem cells: pathways and consequences. Nat Rev Mol Cell Biol 12:198–202PubMedCrossRefGoogle Scholar
  66. Manning G, Rothkamm K (2013) Deoxyribonucleic acid damage-associated biomarkers of ionising radiation: current status and future relevance for radiology and radiotherapy. Br J Radiol 86:20130173PubMedPubMedCentralCrossRefGoogle Scholar
  67. Mansour WY, Bogdanova NV, Kasten-Pisula U, Rieckmann T, Kocher S, Borgmann K, Baumann M, Krause M, Petersen C, Hu H et al (2013b) Aberrant overexpression of miR-421 downregulates ATM and leads to a pronounced DSB repair defect and clinical hypersensitivity in SKX squamous cell carcinoma. Radiother Oncol J Eur Soc Ther Radiol Oncol 106:147–154CrossRefGoogle Scholar
  68. Mansour WY, Borgmann K, Petersen C, Dikomey E, Dahm-Daphi J (2013a) The absence of Ku but not defects in classical non-homologous end-joining is required to trigger PARP1-dependent end-joining. DNA Repair 12:1134–1142PubMedCrossRefGoogle Scholar
  69. Mansour WY, Rhein T, Dahm-Daphi J (2010) The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies. Nucleic Acids Res 38:6065–6077PubMedPubMedCentralCrossRefGoogle Scholar
  70. Mansour WY, Schumacher S, Rosskopf R, Rhein T, Schmidt-Petersen F, Gatzemeier F, Haag F, Borgmann K, Willers H, Dahm-Daphi J (2008) Hierarchy of nonhomologous end-joining, single-strand annealing and gene conversion at site-directed DNA double-strand breaks. Nucleic Acids Res 36:4088–4098PubMedPubMedCentralCrossRefGoogle Scholar
  71. Marechal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harbor Perspect Biol 5Google Scholar
  72. Martins RG, Parvathaneni U, Bauman JE, Sharma AK, Raez LE, Papagikos MA, Yunus F, Kurland BF, Eaton KD, Liao JJ et al (2013) Cisplatin and radiotherapy with or without Erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase ii trial. J Clin Oncol Official J Am Soc Clin OncolGoogle Scholar
  73. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N et al (2015) DNA-repair defects and olaparib in metastatic prostate cancer. N Eng J Med 373:1697–1708CrossRefGoogle Scholar
  74. Mathews LA, Cabarcas SM, Hurt EM, Zhang X, Jaffee EM, Farrar WL (2011) Increased expression of DNA repair genes in invasive human pancreatic cancer cells. Pancreas 40:730–739PubMedPubMedCentralCrossRefGoogle Scholar
  75. Maugeri-Sacca M, Vici P, Di Lauro L, Barba M, Amoreo CA, Gallo E, Mottolese M, De Maria R (2014) Cancer stem cells: are they responsible for treatment failure? Future Oncol 10:2033–2044PubMedCrossRefGoogle Scholar
  76. Maynard S, Swistowska AM, Lee JW, Liu Y, Liu ST, Da Cruz AB, Rao M, de Souza-Pinto NC, Zeng X, Bohr VA (2008) Human embryonic stem cells have enhanced repair of multiple forms of DNA damage. Stem Cells 26:2266–2274PubMedPubMedCentralCrossRefGoogle Scholar
  77. McCord AM, Jamal M, Williams ES, Camphausen K, Tofilon PJ (2009) CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin Cancer Res Official J Am Assoc Cancer Res 15:5145–5153CrossRefGoogle Scholar
  78. McNeely S, Beckmann R, Bence Lin AK (2014) CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy. Pharmacol Ther 142:1–10PubMedCrossRefGoogle Scholar
  79. Menegakis A, von Neubeck C, Yaromina A, Thames H, Hering S, Hennenlotter J, Scharpf M, Noell S, Krause M, Zips D et al (2015) gammaH2AX assay in ex vivo irradiated tumour specimens: a novel method to determine tumour radiation sensitivity in patient-derived material. Radiother Oncol J Eur Soc Ther Radiol OncolGoogle Scholar
  80. Menegakis A, De Colle C, Yaromina A, Hennenlotter J, Stenzl A, Scharpf M, Fend F, Noell S, Tatagiba M, Brucker S et al (2015) Residual gammaH2AX foci after ex vivo irradiation of patient samples with known tumour-type specific differences in radio-responsiveness. Radiother Oncol J Eur Soc Ther Radiol OncolGoogle Scholar
  81. Mesia R, Henke M, Fortin A, Minn H, Yunes Ancona AC, Cmelak A, Markowitz AB, Hotte SJ, Singh S, Chan AT et al (2015) Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 16:208–220PubMedCrossRefGoogle Scholar
  82. Möckelmann N, Rieckmann T, Busch CJ, Becker B, Gleißner L, Hoffer K, Omniczynski M, Steinmeister L, Laban S, Grénman R et al (2016) Effect of sorafenib on cisplatin-based chemoradiation in head and neck cancer cells. Oncotarget doi:  10.18632/oncotarget.8275
  83. Moeller BJ, Yordy JS, Williams MD, Giri U, Raju U, Molkentine DP, Byers LA, Heymach JV, Story MD, Lee JJ et al (2011) DNA repair biomarker profiling of head and neck cancer: Ku80 expression predicts locoregional failure and death following radiotherapy. Clin Cancer Res Official J Am Assoc Cancer Res 17:2035–2043CrossRefGoogle Scholar
  84. Morgan MA, Lawrence TS (2015) Molecular pathways: overcoming radiation resistance by targeting DNA damage response pathways. Clin Cancer Res Official J Am Assoc Cancer Res 21:2898–2904CrossRefGoogle Scholar
  85. Myllynen L, Rieckmann T, Dahm-Daphi J, Kasten-Pisula U, Petersen C, Dikomey E, Kriegs M (2011) In tumor cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status. Radiother Oncol J Eur Soc Ther Radiol Oncol 101:147–151CrossRefGoogle Scholar
  86. Naipal KA, Verkaik NS, Ameziane N, van Deurzen CH, Ter Brugge P, Meijers M, Sieuwerts AM, Martens JW, O’Connor MJ, Vrieling H et al (2014) Functional ex vivo assay to select homologous recombination-deficient breast tumors for PARP inhibitor treatment. Clin Cancer Res Official J Am Assoc Cancer Res 20:4816–4826CrossRefGoogle Scholar
  87. Noel G, Godon C, Fernet M, Giocanti N, Megnin-Chanet F, Favaudon V (2006) Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol Cancer Ther 5:564–574PubMedCrossRefGoogle Scholar
  88. Olive PL (2009) Impact of the comet assay in radiobiology. Mutat Res 681:13–23PubMedCrossRefGoogle Scholar
  89. Orthwein A, Fradet-Turcotte A, Noordermeer SM, Canny MD, Brun CM, Strecker J, Escribano-Diaz C, Durocher D (2014) Mitosis inhibits DNA double-strand break repair to guard against telomere fusions. Science 344:189–193PubMedCrossRefGoogle Scholar
  90. Ostling O, Johanson KJ (1984) Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells. Biochem Biophys Res Commun 123:291–298PubMedCrossRefGoogle Scholar
  91. Parplys AC, Kratz K, Speed MC, Leung SG, Schild D, Wiese C (2014) RAD51AP1-deficiency in vertebrate cells impairs DNA replication. DNA Repair 24:87–97PubMedCrossRefGoogle Scholar
  92. Parplys AC, Petermann E, Petersen C, Dikomey E, Borgmann K (2012) DNA damage by X-rays and their impact on replication processes. Radiother Oncol J Eur Soc Ther Radiol Oncol 102:466–471CrossRefGoogle Scholar
  93. Parplys AC, Seelbach JI, Becker S, Behr M, Jend C, Mansour WY, Joosse S, Stuerzbecher HW, Pospiech H, Petersen C et al (2015a) High levels of RAD51 perturb DNA replication elongation and cause unscheduled origin firing due to impaired CHK1 activation. Cell CycleGoogle Scholar
  94. Parplys AC, Zhao W, Sharma N, Groesser T, Liang F, Maranon DG, Leung SG, Grundt K, Dray E, Idate R et al (2015b) NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability. Nucleic Acids ResGoogle Scholar
  95. Pearl LH, Schierz AC, Ward SE, Al-Lazikani B, Pearl FM (2015) Therapeutic opportunities within the DNA damage response. Nat Rev Cancer 15:166–180PubMedCrossRefGoogle Scholar
  96. Pernot E, Hall J, Baatout S, Benotmane MA, Blanchardon E, Bouffler S, El Saghire H, Gomolka M, Guertler A, Harms-Ringdahl M et al (2012) Ionizing radiation biomarkers for potential use in epidemiological studies. Mutat Res 751:258–286PubMedCrossRefGoogle Scholar
  97. Pires IM, Olcina MM, Anbalagan S, Pollard JR, Reaper PM, Charlton PA, McKenna WG, Hammond EM (2012) Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. Br J Cancer 107:291–299PubMedPubMedCentralCrossRefGoogle Scholar
  98. Pramana J, Van den Brekel MW, van Velthuysen ML, Wessels LF, Nuyten DS, Hofland I, Atsma D, Pimentel N, Hoebers FJ, Rasch CR et al (2007) Gene expression profiling to predict outcome after chemoradiation in head and neck cancer. Int J Radiat Oncol Biol Phys 69:1544–1552PubMedCrossRefGoogle Scholar
  99. Qvarnstrom OF, Simonsson M, Johansson KA, Nyman J, Turesson I (2004) DNA double strand break quantification in skin biopsies. Radiother Oncol J Eur Soc Ther Radiol Oncol 72:311–317CrossRefGoogle Scholar
  100. Ropolo M, Daga A, Griffero F, Foresta M, Casartelli G, Zunino A, Poggi A, Cappelli E, Zona G, Spaziante R et al (2009) Comparative analysis of DNA repair in stem and nonstem glioma cell cultures. Mol Cancer Res MCR 7:383–392PubMedCrossRefGoogle Scholar
  101. Rothkamm K, Barnard S, Moquet J, Ellender M, Rana Z, Burdak-Rothkamm S (2015) DNA damage foci: meaning and significance. Environ Mol Mutagen 56:491–504PubMedCrossRefGoogle Scholar
  102. Rothkamm K, Crosbie JC, Daley F, Bourne S, Barber PR, Vojnovic B, Cann L, Rogers PA (2012) In situ biological dose mapping estimates the radiation burden delivered to ‘spared’ tissue between synchrotron X-ray microbeam radiotherapy tracks. PLoS ONE 7:e29853PubMedPubMedCentralCrossRefGoogle Scholar
  103. Rothkamm K, Kruger I, Thompson LH, Lobrich M (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23:5706–5715PubMedPubMedCentralCrossRefGoogle Scholar
  104. Rothkamm K, Lobrich M (2002) Misrepair of radiation-induced DNA double-strand breaks and its relevance for tumorigenesis and cancer treatment (review). Int J Oncol 21:433–440PubMedGoogle Scholar
  105. Rothkamm K, Lobrich M (2003) Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci USA 100:5057–5062PubMedPubMedCentralCrossRefGoogle Scholar
  106. Rube CE, Dong X, Kuhne M, Fricke A, Kaestner L, Lipp P, Rube C (2008) DNA double-strand break rejoining in complex normal tissues. Int J Radiat Oncol Biol Phys 72:1180–1187PubMedCrossRefGoogle Scholar
  107. Saker J, Kriegs M, Zenker M, Heldt JM, Eke I, Pietzsch HJ, Grenman R, Cordes N, Petersen C, Baumann M et al (2013) Inactivation of HNSCC cells by 90Y-labeled cetuximab strictly depends on the number of induced DNA double-strand breaks. J Nucl Med Official Pub Soc Nucl Med 54:416–423Google Scholar
  108. Sarbajna S, Davies D, West SC (2014) Roles of SLX1-SLX4, MUS81-EME1, and GEN1 in avoiding genome instability and mitotic catastrophe. Genes Dev 28:1124–1136PubMedPubMedCentralCrossRefGoogle Scholar
  109. Shin KH, Kang MK, Kim RH, Kameta A, Baluda MA, Park NH (2006) Abnormal DNA end-joining activity in human head and neck cancer. Int J Mol Med 17:917–924PubMedGoogle Scholar
  110. Shinohara A, Shinohara M, Ohta T, Matsuda S, Ogawa T (1998) Rad52 forms ring structures and co-operates with RPA in single-strand DNA annealing. Genes Cells Devoted Mol Cell Mech 3:145–156CrossRefGoogle Scholar
  111. Signore M, Pelacchi F, di Martino S, Runci D, Biffoni M, Giannetti S, Morgante L, De Majo M, Petricoin EF, Stancato L et al (2014) Combined PDK1 and CHK1 inhibition is required to kill glioblastoma stem-like cells in vitro and in vivo. Cell Death Dis 5:e1223PubMedPubMedCentralCrossRefGoogle Scholar
  112. Somaiah N, Yarnold J, Daley F, Pearson A, Gothard L, Rothkamm K, Helleday T (2012) The relationship between homologous recombination repair and the sensitivity of human epidermis to the size of daily doses over a 5-week course of breast radiotherapy. Clinical Cancer Res Official J Am Assoc Cancer Res 18:5479–5488CrossRefGoogle Scholar
  113. Sorensen CS, Syljuasen RG (2012) Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res 40:477–486PubMedCrossRefGoogle Scholar
  114. Spitzner M, Emons G, Kramer F, Gaedcke J, Rave-Frank M, Scharf JG, Burfeind P, Becker H, Beissbarth T, Ghadimi BM et al (2010) A gene expression signature for chemoradiosensitivity of colorectal cancer cells. Int J Radiat Oncol Biol Phys 78:1184–1192PubMedCrossRefGoogle Scholar
  115. Spivak G (2015) Nucleotide excision repair in humans. DNA repairGoogle Scholar
  116. Stegeman H, Span PN, Cockx SC, Peters JP, Rijken PF, van der Kogel AJ, Kaanders JH, Bussink J (2013) EGFR-inhibition enhances apoptosis in irradiated human head and neck xenograft tumors independent of effects on DNA repair. Radiat Res 180:414–421PubMedCrossRefGoogle Scholar
  117. Sulli G, Di Micco R, d’Adda di Fagagna F (2012) Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer. Nat Rev Cancer 12:709–720PubMedCrossRefGoogle Scholar
  118. Sung P, Klein H (2006) Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 7:739–750PubMedCrossRefGoogle Scholar
  119. Syljuasen RG, Hasvold G, Hauge S, Helland A (2015) Targeting lung cancer through inhibition of checkpoint kinases. Front Genet 6:70PubMedPubMedCentralGoogle Scholar
  120. Tennstedt P, Fresow R, Simon R, Marx A, Terracciano L, Petersen C, Sauter G, Dikomey E, Borgmann K (2013) RAD51 overexpression is a negative prognostic marker for colorectal adenocarcinoma. Int J Cancer 132:2118–2126PubMedCrossRefGoogle Scholar
  121. Terasawa M, Shinohara A, Shinohara M (2014) Double-strand break repair-adox: restoration of suppressed double-strand break repair during mitosis induces genomic instability. Cancer Sci 105:1519–1525PubMedPubMedCentralCrossRefGoogle Scholar
  122. Tinhofer I, Niehr F, Konschak R, Liebs S, Munz M, Stenzinger A, Weichert W, Keilholz U, Budach V (2015) Next-generation sequencing: hype and hope for development of personalized radiation therapy? Radiat Oncol 10:183PubMedPubMedCentralCrossRefGoogle Scholar
  123. Toulany M, Kasten-Pisula U, Brammer I, Wang S, Chen J, Dittmann K, Baumann M, Dikomey E, Rodemann HP (2006) Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res Official J Am Assoc Cancer Res 12:4119–4126CrossRefGoogle Scholar
  124. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376:235–244PubMedCrossRefGoogle Scholar
  125. UNSCEAR (2000) Sources and Effects of Ionizing Radiation: Annex F: DNA repair and mutagenesis.United Nations scientific committee on the effects of atomic radiation.Google Scholar
  126. Venere M, Hamerlik P, Wu Q, Rasmussen RD, Song LA, Vasanji A, Tenley N, Flavahan WA, Hjelmeland AB, Bartek J et al (2014) Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ 21:258–269PubMedCrossRefGoogle Scholar
  127. Wang Q, Gao F, May WS, Zhang Y, Flagg T, Deng X (2008) Bcl2 negatively regulates DNA double-strand-break repair through a nonhomologous end-joining pathway. Mol Cell 29:488–498PubMedPubMedCentralCrossRefGoogle Scholar
  128. Wang M, Morsbach F, Sander D, Gheorghiu L, Nanda A, Benes C, Kriegs M, Krause M, Dikomey E, Baumann M et al (2011) EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks. Cancer Res 71:6261–6269PubMedPubMedCentralCrossRefGoogle Scholar
  129. Wang H, Perrault AR, Takeda Y, Qin W, Wang H, Iliakis G (2003) Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res 31:5377–5388PubMedPubMedCentralCrossRefGoogle Scholar
  130. Weinstock DM, Brunet E, Jasin M (2007) Formation of NHEJ-derived reciprocal chromosomal translocations does not require Ku70. Nat Cell Biol 9:978–981PubMedPubMedCentralCrossRefGoogle Scholar
  131. Welzel N, Le T, Marculescu R, Mitterbauer G, Chott A, Pott C, Kneba M, Du MQ, Kusec R, Drach J et al (2001) Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma. Cancer Res 61:1629–1636PubMedGoogle Scholar
  132. West CM, Davidson SE, Roberts SA, Hunter RD (1993) Intrinsic radiosensitivity and prediction of patient response to radiotherapy for carcinoma of the cervix. Br J Cancer 68:819–823PubMedPubMedCentralCrossRefGoogle Scholar
  133. Wyatt HD, West SC (2014) Holliday junction resolvases. Cold Spring Harbor Perspect Biol 6:a023192CrossRefGoogle Scholar
  134. Ying S, Hamdy FC, Helleday T (2012) Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. Cancer Res 72:2814–2821PubMedCrossRefGoogle Scholar
  135. Zeman MK, Cimprich KA (2014) Causes and consequences of replication stress. Nature Cell Biol 16:2–9PubMedPubMedCentralCrossRefGoogle Scholar
  136. Zhang P, Wei Y, Wang L, Debeb BG, Yuan Y, Zhang J, Yuan J, Wang M, Chen D, Sun Y et al (2014) ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nature Cell Biol 16:864–875PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Kerstin Borgmann
    • 1
  • Sabrina Köcher
    • 1
  • Malte Kriegs
    • 1
  • Wael Yassin Mansour
    • 1
  • Ann Christin Parplys
    • 1
  • Thorsten Rieckmann
    • 1
    • 2
  • Kai Rothkamm
    • 1
    Email author
  1. 1.Laboratory of Radiobiology and Experimental Radio-OncologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Department of Otorhinolaryngology and Head and Neck SurgeryUniversity Medical Center Hamburg-EppendorfHamburgGermany

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