Open access

DNA Repair Based Therapy in Oncology and Neurodegeneration

Written By

Turgay Isbir, Uzay Gormus, Ozlem Timirci-Kahraman, Arzu Ergen, Altay Burak Dalan, Seda Gulec-Yilmaz and Hande Atasoy

Submitted: June 13th, 2014 Published: November 18th, 2015

DOI: 10.5772/59711

Chapter metrics overview

1,507 Chapter Downloads

View Full Metrics

1. Introduction

There are various types of DNA damages as well as the presence of sophisticated processes utilized by the cells to maintain the integrity of genome. It has been shown that DNA damage is a usual event which is also underlying cause of many disorders such as cancer and other inherited or acquired pathologies. There are many endogenous and exogenous sources which cause DNA damages interfering with genome [1].

In response to genotoxic stress which can be mainly caused by various chemicals, reactive cellular metabolites and ionizing/UV radiation, DNA repair pathways and cell cycle check-points can be activated, allowing the cell to repair and prevent the transmission of damaged and/or incompletely replicated chromosomes. The balance between cell cycle arrest, DNA repair and the initiation of cell death can determine whether DNA damage is compatible with cell survival or require elimination of the damaged cell by apoptosis. Defects of DNA repair pathways and cell cycle checkpoints may cause susceptibility to DNA damages, genomic defects, hypersensitivity to cellular stress and resistance to apoptosis, which all characterize cancer cells [2].

Repair of DNA is critical for cell growth, proliferation and for organ development. Genome stability and maintenance require several biochemical pathways involving many different proteins that are having roles in specific DNA repair pathways. Loss of function in these repair proteins may lead to pathologies including growth and developmental defects, like immunodeficiency, cancer and neurodegeneration [3]. As known, cancer is a disease of excessive cell proliferation, whereas neurodegeneration is a disease of excessive cell dysfunction and death. Those opposite cellular effects can arise from defects of common and/or related processes [4]. DNA repair enable cancer cells to additively accumulate genomic alterations and change into more aggressive phenotypes. As DNA repair pathways are frequently altered in cancer; during anticancer therapies alterations in DNA repair should also be considered [5]. So it may therefore be most effective to search primarily for genetic alterations in those pathways first.

Genomic integrity is important for the survival and is controlled by DNA damage response (DDR) network, this is a complicated signal transduction system sensing DNA damage and recruit repair factors; DDR senses different types of damages and coordinates the responses including cell cycle, apoptosis, senescence and DNA repair processes [6,7]. As it is now known, aging, dementia, and cancer share altered cellular functions in response to DNA damage and/or genotoxic stress. The molecular machinery involved in neural function in neurodegenerative diseases may be shared with oncogenic pathways; so both may be affected by common signaling pathways regulating the balance of cell survival and death [3]. For those regulations to occur, cell cycle check point proteins are extremely important, among those p53 is the most significant because of its role in stopping cell cycle in G0/G1 and G2/M phases, it helps to determine whether the cell will go to apoptosis or DNA repair will occur. Those prevent inappropriate DNA replication, whereas the G2/M checkpoint prevents cells with DNA damage from entering mitosis. Loss of p53 may increase risk of carcinogenesis, whereas specific gain-of-function in its alleles reduces the incidence of cancer but accelerate aging [3]. The p53 is only one of the targets that may involve in both cancers and aging-related neurological diseases. For instance, in mouse models, experiments showed that the withdrawal of the important myc oncogene was resulting in regression of osteosarcomas, epidermal papillomas and lymphomas [8,9]. As those kinds of gene therapies are now usual for experimental area, in this chapter, we aimed to focus on the current therapeutic approaches focusing on the DNA repair in cancer and neurodegenerative diseases.

DDR is related to a pair of related protein kinases called ATM and ATR and both are activated by DNA damage. ATM works with its regulator MRN complex (MRE11, Rad50-NBS1) by sensing the double-strand breaks (DSBs) [10]. ATR has also its regulator ATRIP (ATR-interacting protein) sensing single-strand DNA (ssDNA). Both of them has many common substrates including Chk1 and Chk2 initiating a cascade that results in cell cycle arrest and DNA repair. Chk1 and Chk2 are serine/threonine kinases; Chk1 is responsible for initiating cell cycle arrest to allow time for DNA repair. After its activation, Chk1 prevents cells from entering S phase [11,12]. Chk2 has a similar effect and is activated by phosphorylation by ATM after DSB [13,14]. In this cascade, phosphorylation of histone H2AX on Ser139 by ATM and ATR leads to the accumulation of repair proteins on DSBs sites [15-17]. Many proteins involved in DDR contain specific H2AX-recognition domains such as BRCT domains (C-terminal domain of BRCA1) [18,19].

Depending on the phase of the cell cycle, there are two major intracellular DNA DSB repair pathways: homologous recombination (HR) or non-homologous-end joining (NHEJ) [1,20]. As chromosomes are duplicated during S-phase of the cell cycle, double strand breaks (DSBs) during S/G2 can be repaired without any loss of information, by recombination between the damaged and its homologous undamaged counterpart. This process is known as homologous recombination (HR), and requires the activity of a number of proteins including BRCA1, BRCA2, XRCC2, XRCC3, and RAD51 [21]. Homozygous HR mutants are rarely survive to birth. Patients carrying such mutations usually have developmental disorders like Fanconi anemia [22]. Homologous recombination uses a sister chromatid in S and G2 phases as a template; NHEJ is an error-prone method of directly ligating the DSB ends in G0 and G1 phases. HR involves BRCA1, BRCA2 and Rad51 proteins and NHEJ involves Ku70/80, the DNA-PK, and DNA ligase IV [1]. During migration and differentiation, there is dependence on NHEJ pathways, so mutations in the NHEJ pathway can result in loss of neuroprogenitor cells, cortical neurons and finally results in microcephaly.

As an example to neurological disorders caused by DSB repair, the severity of the disease in ataxia telangiectasia usually correlates with the nature of the mutation, the amount of active ATM protein within the cells of the patient; as it is a disease with the symptoms of immunodeficiency, sterility, radiosensitivity, cancer predisposition [23,24]. In those cases, loss of ATM results primarily in neuronal dysfunction and ataxia rather than microcephaly. If ATM signal fails, neurons may escape apoptosis and with their unrepaired DSBs they will stay in a dysfunctional state causing juvenile neuropathology. Late-onset progressive neuropathologies, like ataxia telangiectasia, are under debate yet probably depending on the cumulative effects of DNA damages [25].

Single-strand breaks (SSBs) are 3 orders of magnitude more frequent than DSBs. SSBs are usually repaired by the SSBR and NER pathways. Nucleotide-excision repair (NER) is mainly responsible for repairing pyrimidine dimers having important roles during G1 phase to remove bulky lesions, caused for example by ultraviolet irradiation [1]. But if those pathways are defective, they can trigger apoptosis by blocking the progression of RNA polymerases [26]. The defects in the repair of SSBs are less likely to cause developmental defects, but they are related to neurodegeneration and premature ageing. Deficiencies in single-strand break repair (SSBR) may lead to cellular sensitivity to radiation, oxidative stress and base damaging agents. As poly-ADP-ribose polymerase (PARP1) is the sensor of chromosomal SSBs, it hauls SSBR proteins to the sites of DNA damage [27]. Neuronal cells seem to be particularly sensitive to PARP-induced cell death as shown in cerebral ischaemia experiments [28].

DNA-damaging agents are the corner-stones for the treatment of solid tumors. It is now known that tumors that do not respond to DNA-damaging treatment had proficient DNA repair processes [29,30]. DNA damaging genotoxic therapeutics can be divided into groups due to their mechanism of action and type of damage induced. Alkylating agents and platinum-based agents directly effect DNA to induce bulky DNA damage and those are repaired by the nucleotide excision repair pathway (NER) [1,31,32]. Direct methylating agents cause damages that are repaired mainly via the base excision repair pathway (BER) [31]. DSBs are considered as most toxic forms of DNA damages, induction of DSB via radiation or radio-mimetics is an effective method to induce cellular death. DNA metabolism can also be targetted and DNA intercalating agents, topoisomerase poisons and antimetabolites can be used for this purpose [32].

ATM kinase has been a target for the development of novel anticancer agents. The disease associated with ATM mutation is known as ataxia telangiectasia, an autosomal recessive neurological disorder characterized by cerebellar ataxia and oculocutaneous telangiectasia [33]. This disease has symptoms of growth retardation, premature aging and insulin resistance; patients are known to exhibit hypersensitivity to ionizing radiation. So ATM inhibitors are thought to act as radiosensitizer and/or chemosensitizer [34]. Several ATM and ATM/ATR specific inhibitors have been recently developed: LY294002, KU-55933, KU-60019, CP466722, aminopyrazines [35-37]. As p53 is one of the major substrates for ATM, targetting p53 function also enhances cell sensitivity to ATR disruption.

Inhibitors of poly-ADP-ribosepolymerase (PARP) enzyme, that is normally involved in DNA repair, are also used in DNA repair-based therapies. PARP1 inhibitors are used in the treatment of BRCA1- or BRCA2- defective cancers. ADP-ribosylation is also important in DNA repair and genome stability [5]. As it is known, the BRCA1 and BRCA2 genes play essential roles in HR-mediated DSB repair, PARP1 inhibition induces DNA damages. BRCA1/2- defective cells are sensitive to PARP1 inhibition, but BRCA1/2-proficient cells are resistant [38]. However, although there are main hypotheses, the precise mechanism through which PARP1 inhibition leads to cytotoxicity in HR-defective cells is not exactly known yet. As it is found that PARP1 inhibitors were active against HR-defective tumors, it was thought that their effect could be increased by combination therapies with other genotoxic drugs.

miRNAs are also promising agents to improve efficacy of cancer therapy due to their ability to target DDR components and control cellular responses to DNA damaging agents. For instance, it is known that inhibition of ATM by miR-101, miR-100 and miR-421 or inhibition of DNA-PKcs by miR-101 may cause increased cellular sensitivity to IR [39,40]. It is known that some miRNAs can target multiple genes involved in DDR, so it is thought that modulating endogenous miRNA expression may be a promising way to overcome chemoresistance in cancer treatment [41].


2. Conclusion

Cancer and neurodegeneration are diseases occured because of genomic instability accumulated in large regions of the genome. Many of these abnormalities are eligibilities of inaccurate joining of double-strand break ends, resulting from disruption of DNA repair mechanism [42]. These defects are defined such as single nucleotide polymorphisms, mutations, copy number changes or chromosomal realignments causes inactivation of DNA-repair, tumour-suppressor and proapoptotic genes, leading to defects in the repair of DNA damage. Accordingly, there is a need for diagnostic tests of DNA repair deficiency in clinical trials. Recent studies indicated correlation between a DNA repair profiling methods and prognosis [43]. Clinical development of DDR inhibitors will be expedited in the future by use of next-generation sequencing of key and novel genes included as well as molecular and functional assays for DDR proficiency to identify phenotypes is likely to respond to this approaches and strategies.


  1. 1. Turgay Isbir, Berna Demircan, Deniz Kirac, Burak Dalan, Uzay Gormus. DNA Repair, Cancer and Cancer Therapy -The Current State of Art. DNA Repair and Human Health. 2011; DOI: 10.5772/24147 279-306.
  2. 2. Ishikawa K, Ishii H, Saito T. DNA Damage-Dependent Cell Cycle Checkpointsand Genomic Stability. DNA and Cell Biology 2006;25(7) 406-411.
  3. 3. Hoeijmakers JH. DNA damage, aging, and cancer, N Engl J Med 2009; 361 1475-1485.
  4. 4. Morris LG, Veeriah S, Chan TA. Genetic determinants at the interface of cancer and neurodegenerative disease. Oncogene 2010;29 3453-3464.
  5. 5. Dietlein F, Thelen L, Reinhardt HC. Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends in Genetics 2014;8 326-339.
  6. 6. Harper JW, Elledge SJ. The DNA damage response: ten years after. Mol Cell 2007;28 739-745.
  7. 7. Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature 2000;408 433-439.
  8. 8. Pelengaris S, Littlewood T, Khan M, Elia G, Evan G. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol Cell 1999; 3(5) 565-77.
  9. 9. Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 1999;4 199–207.
  10. 10. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature 2004;432 316-323.
  11. 11. Bartek J, Lukas J. Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr Opin Cell Biol 2001;13 738-747.
  12. 12. Zhou BBS, Sausville EA. Drug discovery targeting Chk1 and Chk2 kinases. Prog Cell Cycle Res 2003;5 413-421.
  13. 13. Mailand N, Falck J, Lukas C, Syljuâsen RG, Welcker M, Bartek J, Lukas J. Rapid destruction of human Cdc25A in response to DNA damage. Science 2000;288 1425-1429.
  14. 14. Falck J, Mailand N, Syljuåsen RG, Bartek J, Lukas J. The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 2001; 410 842-847.
  15. 15. Rogakou EP. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998;273 5858-5868.
  16. 16. Kouzarides T. SnapShot: histone-modifying enzymes. Cell 2007;131 822.
  17. 17. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol, 2007;14(1) 1025-1040.
  18. 18. Manke IA, Drew ML, Anhco N, Yaffe MB. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 2003;302 636-639.
  19. 19. Falck J, Coates J, Jackson SP. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 2005;434 605-611.
  20. 20. Mimitou EP, Symington LS. Nucleases and helicases take center stage in homologous recombination. Trends Biochem Sci 2009;34 264-272.
  21. 21. Moynahan ME, Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 2010;11 196-207.
  22. 22. Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 2007;44 1-9.
  23. 23. Taylor AM, Byrd PJ. Molecular pathology of ataxia telangiectasia. J Clin Pathol 2005; 58 1009-1015.
  24. 24. Lakin ND, Weber P, Stankovic T, Rottinghaus ST, Taylor AM, Jackson SP. Analysis of the ATM protein in wild-type and ataxia telangiectasia cells. Oncogene 1996;13 2707-2716.
  25. 25. McKinnon PJ. ATM and the molecular pathogenesis of ataxia telangiectasia. Annu Rev Pathol 2012;7 303-321.
  26. 26. Schumacher B. Transcription-blocking DNA damage in aging: a mechanism for hormesis. Bioessays 2009;31 1347-1356.
  27. 27. El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW. A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res 2003;31 5526-5533.
  28. 28. Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 2002; 54 375-429.
  29. 29. Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC; IALT Bio Investigators. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355(10) 983-91.
  30. 30. Oliver TG, Mercer KL, Sayles LC, Burke JR, Mendus D, Lovejoy KS, Cheng MH, Subramanian A, Mu D, Powers S, Crowley D, Bronson RT, Whittaker CA, Bhutkar A, Lippard SJ, Golub T, Thomale J, Jacks T, Sweet-Cordero EA. Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev 2010 15;24(8) 837-52.
  31. 31. Parsons JL, Dianov GL. Co-ordination of base excision repair and genome stability. DNA Repair 2013;12 326-333.
  32. 32. Woods D, Turchi JJ. Chemotherapy induced DNA damage response, Convergence of drugs and pathways. Cancer Biology & Therapy 2013;14(5) 379-389.
  33. 33. Shiloh Y, Kastan MB. ATM: genome stability, neuronal development, and cancer cross paths. Adv Cancer Res 2001;83 209-254.
  34. 34. Sarkaria JN, Eshleman JS. ATM as a target for novel radiosensitizers. Semin Radiat Oncol 2001;11 316-327.
  35. 35. Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NM, Orr AI, Reaper PM, Jackson SP, Curtin NJ, Smith GC. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res 2004; 64(24) 9152-9.
  36. 36. 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(6) 167-73.
  37. 37. Charrier JD, Durrant SJ, Golec JM, Kay DP, Knegtel RM, MacCormick S, Mortimore M, O'Donnell ME, Pinder JL, Reaper PM, Rutherford AP, Wang PS, Young SC, Pollard JR. Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem 2011;54(7) 2320-30.
  38. 38. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434(7035) 917-21.
  39. 39. Ng WL, Yan D, Zhang X, Mo YY, Wang Y. Overexpression of miR-100 is responsible for the lowexpression of ATM in the human glioma cell line: M059J. DNA Repair (Amst) 2010;9 1170-5.
  40. 40. Yan D, Ng WL, Zhang X, Wang P, Zhang Z, Mo YY, Mao H, Hao C, Olson JJ, Curran WJ, Wang Y. Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation. PLoS One 2010;5(7) e11397.
  41. 41. Wang Y, Taniguchi T. MicroRNAs and DNA damage response: Implications for cancer therapy. Cell Cycle 2013;12(1) 32-42.
  42. 42. Liu C, Srihari S, Cao KA, Chenevix-Trench G, Simpson PT, Ragan MA, Khanna KK. A fine-scale dissection of the DNA double-strand break repair machinery and its implications for breast cancer therapy. Nucleic Acids Res 2014;42(10) 6106-27.
  43. 43. Oakman C, Pestrin M, Cantisani E, Licitra S, DeStefanis M, Biganzoli L, Di Leo A. Adjuvant chemotherapy--the dark side of clinical trials. Have we learnt more? Breast. 2009;18(3) 18-24.

Written By

Turgay Isbir, Uzay Gormus, Ozlem Timirci-Kahraman, Arzu Ergen, Altay Burak Dalan, Seda Gulec-Yilmaz and Hande Atasoy

Submitted: June 13th, 2014 Published: November 18th, 2015