Advertisement

DNA Repair in Radiation Oncology

  • R. D. CarruthersEmail author
  • A. J. Chalmers
Living reference work entry

Abstract

The success or failure of radiation oncology treatments depends upon the ability of cancer cells to repair the DNA damage inflicted by ionizing radiation. Unsuccessful DNA repair will result in cancer cell death and therapeutic success, whereas proficient DNA repair within malignant cells will result in treatment failure and clinical recurrence or progression of disease. Therefore, an appreciation of the basic principles of DNA repair is vital to understanding the tumor and normal tissue response to radiotherapy.

This chapter will summarize current knowledge on the response to ionizing radiation-induced DNA damage in malignant and normal tissue and explore the major biological mechanisms responsible for DNA repair in mammalian cells. Furthermore, the chapter will explore recent developments in the modification of radiation resistance in tumors using drugs with the ability to inhibit particular DNA repair pathways in an effort to provide clinically useful tumor specific radiosensitization.

Keywords

DNA repair DNA damage response Ionising radiation 

References

  1. Ahmed SU, Carruthers R, Gilmour L, Yildirim S, Watts C, Chalmers AJ. Selective inhibition of parallel DNA damage response pathways optimizes Radiosensitization of glioblastoma stem-like cells. Cancer Res. 2015;75:4416–28.CrossRefGoogle Scholar
  2. Alvarez-Quilon A, Serrano-Benitez A, Lieberman JA, Quintero C, Sanchez-Gutierrez D, Escudero LM, Cortes-Ledesma F. ATM specifically mediates repair of double-strand breaks with blocked DNA ends. Nat Commun. 2014;5:3347.CrossRefGoogle Scholar
  3. Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421:499–506.CrossRefGoogle Scholar
  4. Banath JP, Macphail SH, Olive PL. Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines. Cancer Res. 2004;64:7144–9.CrossRefGoogle Scholar
  5. Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, Orntoft T, Lukas J, Bartek J. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864–70.Google Scholar
  6. Bentley J, Diggle CP, Harnden P, Knowles MA, Kiltie AE. DNA double strand break repair in human bladder cancer is error prone and involves microhomology-associated end-joining. Nucleic Acids Res. 2004;32:5249–59.CrossRefGoogle Scholar
  7. Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A, Conrad S, Goodarzi AA, Krempler A, Jeggo PA, Lobrich M. ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. EMBO J. 2009;28:3413–27.CrossRefGoogle Scholar
  8. Bothmer A, Robbiani DF, Feldhahn N, Gazumyan A, Nussenzweig A, Nussenzweig MC. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J Exp Med. 2010;207:855–65.CrossRefGoogle Scholar
  9. Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A, Bothmer A, Feldhahn N, Fernandez-Capetillo O, Cao L, Xu X, Deng CX, Finkel T, Nussenzweig M, Stark JM, Nussenzweig A. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell. 2010;141:243–54.CrossRefGoogle Scholar
  10. Carruthers R, Ahmed SU, Strathdee K, Gomez-Roman N, Amoah-Buahin E, Watts C, Chalmers AJ. Abrogation of radioresistance in glioblastoma stem-like cells by inhibition of ATM kinase. Mol Oncol. 2014;9(1):192–203.Google Scholar
  11. Chabot P, Ryu JS, Gorbunova V, Belda C, Ball D, Kio EA, Mehta M, Papp K, Qin Q, Qian J, Holen KD, Giranda VL, Suh JH. Results of a randomized, global, multi-center study of whole-brain radiation therapy (WBRT) plus veliparib or placebo in patients (pts) with brain metastases (BM) from non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33:2021.CrossRefGoogle Scholar
  12. Dahm K. Functions and regulation of human Artemis in double strand break repair. J Cell Biochem. 2007;100:1346–51.CrossRefGoogle Scholar
  13. Defazio LG, Stansel RM, Griffith JD, Chu G. Synapsis of DNA ends by DNA-dependent protein kinase. EMBO J. 2002;21:3192–200.CrossRefGoogle Scholar
  14. Dungey FA, Loser DA, Chalmers AJ. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-ribose) polymerase: mechanisms and therapeutic potential. Int J Radiat Oncol Biol Phys. 2008;72:1188–97.CrossRefGoogle Scholar
  15. Eggler AL, Inman RB, Cox MM. The Rad51-dependent pairing of long DNA substrates is stabilized by replication protein A. J Biol Chem. 2002;277:39280–8.CrossRefGoogle Scholar
  16. Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies Mckenna W, Muschel RJ, Brunner TB. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012;3:e441.CrossRefGoogle Scholar
  17. Frankenberg D, Frankenberg-Schwager M, Blocher D, Harbich R. Evidence for DNA double-strand breaks as the critical lesions in yeast cells irradiated with sparsely or densely ionizing radiation under oxic or anoxic conditions. Radiat Res. 1981;88:524–32.CrossRefGoogle Scholar
  18. Golding SE, Rosenberg E, Adams BR, Wignarajah S, Beckta JM, O’Connor MJ, Valerie K. Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Cell Cycle. 2012;11:1167–73.CrossRefGoogle Scholar
  19. Goodarzi AA, Yu Y, Riballo E, Douglas P, Walker SA, Ye R, Harer C, Marchetti C, Morrice N, Jeggo PA, Lees-Miller SP. DNA-PK autophosphorylation facilitates Artemis endonuclease activity. EMBO J. 2006;25:3880–9.CrossRefGoogle Scholar
  20. Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Lobrich M, Jeggo PA. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell. 2008;31:167–77.CrossRefGoogle Scholar
  21. Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science. 2008;319:1352–5.CrossRefGoogle Scholar
  22. Helleday T, Lo J, Van Gent DC, Engelward BP. DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair (Amst). 2007;6:923–35.CrossRefGoogle Scholar
  23. Jeggo PA, Geuting V, Lobrich M. The role of homologous recombination in radiation-induced double-strand break repair. Radiother Oncol. 2011;101:7–12.CrossRefGoogle Scholar
  24. Lin FL, Sperle K, Sternberg N. Model for homologous recombination during transfer of DNA into mouse L cells: role for DNA ends in the recombination process. Mol Cell Biol. 1984;4:1020–34.CrossRefGoogle Scholar
  25. Lourenco LM, Jiang Y, Drobnitzky N, Green M, Cahill F, Patel A, Shanneik Y, Moore J, Ryan AJ. PARP inhibition combined with thoracic irradiation exacerbates esophageal and skin toxicity in C57BL6 mice. Int J Radiat Oncol Biol Phys. 2018;100:767–75.CrossRefGoogle Scholar
  26. Malkova A, Ivanov EL, Haber JE. Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication. Proc Natl Acad Sci U S A. 1996;93:7131–6.CrossRefGoogle Scholar
  27. Mari PO, Florea BI, Persengiev SP, Verkaik NS, Bruggenwirth HT, Modesti M, Giglia-Mari G, Bezstarosti K, Demmers JA, Luider TM, Houtsmuller AB, Van Gent DC. Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4. Proc Natl Acad Sci U S A. 2006;103:18597–602.CrossRefGoogle Scholar
  28. Moding EJ, Lee CL, Castle KD, Oh P, Mao L, Zha S, Min HD, Ma Y, Das S, Kirsch DG. Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium. J Clin Invest. 2014;124:3325–38.CrossRefGoogle Scholar
  29. Nassif N, Penney J, Pal S, Engels WR, Gloor GB. Efficient copying of nonhomologous sequences from ectopic sites via P-element-induced gap repair. Mol Cell Biol. 1994;14:1613–25.CrossRefGoogle Scholar
  30. Nimonkar AV, Ozsoy AZ, Genschel J, Modrich P, Kowalczykowski SC. Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair. Proc Natl Acad Sci U S A. 2008;105:16906–11.CrossRefGoogle Scholar
  31. Nimonkar AV, Genschel J, Kinoshita E, Polaczek P, Campbell JL, Wyman C, Modrich P, Kowalczykowski SC. BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev. 2011;25:350–62.CrossRefGoogle Scholar
  32. Oing C, Tennstedt P, Simon R, Volquardsen J, Borgmann K, Bokemeyer C, Petersen C, Dikomey E, Rothkamm K, Mansour WY. BCL2-overexpressing prostate cancer cells rely on PARP1-dependent end-joining and are sensitive to combined PARP inhibitor and radiation therapy. Cancer Lett. 2018;423:60–70.CrossRefGoogle Scholar
  33. Prevo R, Fokas E, Reaper PM, Charlton PA, Pollard JR, Mckenna WG, Muschel RJ, Brunner TB. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. 2012;13:1072–81.CrossRefGoogle Scholar
  34. Radford IR. The level of induced DNA double-strand breakage correlates with cell killing after X-irradiation. Int J Radiat Biol Relat Stud Phys Chem Med. 1985;48:45–54.CrossRefGoogle Scholar
  35. Reaper PM, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA, Golec JM, Pollard JR. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011;7:428–30.CrossRefGoogle Scholar
  36. Riballo E, Kuhne M, Rief N, Doherty A, Smith GC, Recio MJ, Reis C, Dahm K, Fricke A, Krempler A, Parker AR, Jackson SP, Gennery A, Jeggo PA, Lobrich M. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell. 2004;16:715–24.CrossRefGoogle Scholar
  37. Roth DB, Wilson JH. Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction. Mol Cell Biol. 1986;6:4295–304.CrossRefGoogle Scholar
  38. Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, Baer R, Lukas J, Jackson SP. Human CtIP promotes DNA end resection. Nature. 2007;450:509–14.CrossRefGoogle Scholar
  39. Schneider L, Fumagalli M, D’Adda Di Fagagna F. Terminally differentiated astrocytes lack DNA damage response signaling and are radioresistant but retain DNA repair proficiency. Cell Death Differ. 2012;19:582–91.CrossRefGoogle Scholar
  40. Shibata A, Conrad S, Birraux J, Geuting V, Barton O, Ismail A, Kakarougkas A, Meek K, Taucher-Scholz G, Lobrich M, Jeggo PA. Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J. 2011;30:1079–92.CrossRefGoogle Scholar
  41. Shibata A, Moiani D, Arvai AS, Perry J, Harding SM, Genois MM, Maity R, Van Rossum-Fikkert S, Kertokalio A, Romoli F, Ismail A, Ismalaj E, Petricci E, Neale MJ, Bristow RG, Masson JY, Wyman C, Jeggo PA, Tainer JA. DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol Cell. 2014;53:7–18.CrossRefGoogle Scholar
  42. Taylor AM, Harnden DG, Arlett CF, Harcourt SA, Lehmann AR, Stevens S, Bridges BA. Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity. Nature. 1975;258:427–9.CrossRefGoogle Scholar
  43. Uematsu N, Weterings E, Yano K, Morotomi-Yano K, Jakob B, Taucher-Scholz G, Mari PO, Van Gent DC, Chen BP, Chen DJ. Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks. J Cell Biol. 2007;177:219–29.CrossRefGoogle Scholar
  44. Vance S, Liu E, Zhao L, Parsels JD, Parsels LA, Brown JL, Maybaum J, Lawrence TS, Morgan MA. Selective radiosensitization of p53 mutant pancreatic cancer cells by combined inhibition of Chk1 and PARP1. Cell Cycle. 2011;10:4321–9.CrossRefGoogle Scholar
  45. Walker JR, Corpina RA, Goldberg J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature. 2001;412:607–14.CrossRefGoogle Scholar
  46. Wang H, Perrault AR, Takeda Y, Qin W, Wang H, Iliakis G. Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res. 2003;31:5377–88.CrossRefGoogle Scholar
  47. Ward JF. Radiation-induced strand breakage in DNA. Basic Life Sci. 1975;5B:471–2.PubMedGoogle Scholar
  48. Wold MS. Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem. 1997;66:61–92.CrossRefGoogle Scholar
  49. You Z, Bailis JM, Johnson SA, Dilworth SM, Hunter T. Rapid activation of ATM on DNA flanking double-strand breaks. Nat Cell Biol. 2007;9:1311–8.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institute of Cancer Sciences, Wolfson Wohl Cancer Research CentreUniversity of GlasgowGlasgowUK

Personalised recommendations