DNA Damage Response: From Tumourigenesis to Therapy


The deoxyribonucleic acid (DNA) damage response (DDR) pathway is a surveillance network, whereby lesions are eliminated from DNA to ensure genomic integrity. The DDR detects aberrant DNA and chromosomal structures and elicits a multifaceted response network to coordinate multiple cellular processes, including regulation of the cell cycle, DNA repair, replication and, under certain circumstances, the triggering of programmed cell death. However, when the DDR is dysregulated, genomic integrity is not ensured, which may lead to tumourigenesis. Paradoxically, although genomic instability is a hallmark of many cancers, many conventional cancer treatments elicit the generation of additional DNA damage to exploit inherent DDR faults present in tumour cells. In addition, new‚Äźtargeted DDR inhibitors are currently being developed to enhance therapeutic indexes, including those that are synthetically lethal in particular tumour cell types, providing exciting new therapeutic avenues for cancer treatment. The challenge is how to identify the patients most receptive to these treatments.

Key Concepts:

  • Genome stability is critical to prevent tumourigenesis.

  • Cell cycle checkpoints and DNA repair exist to prevent faulty genetic information from passing onto daughter cells.

  • Many cancer types exhibit defective DNA repair pathways.

  • DNA repair is an ideal therapeutic target for cancer.

  • Cancers exhibit multiple chromosomal alterations.

  • Inherited mutations in DNA repair genes can cause chromosomal instability disorders.

Keywords: DNA damage response; DNA repair; genomic stability; tumourigenesis; synthetic lethality; cell cycle checkpoint; homologous recombination; nonhomologous end joining; cancer

Figure 1.

Schematic representation of the DNA damage response pathway. In this model, DNA damage is recognised by sensors, which transmit the signal to the ATM/ATR protein kinases. ATM‐/ATR‐dependent signals are then transduced to the Chk1 and Chk2 protein kinases by a series of adaptors and signal modifiers. End points for the DNA damage response, including cell cycle arrest, DNA repair, gene transcription and apoptotic cell death, are shown.

Figure 2.

A central role of ATM/ATR in DNA damage checkpoint pathways. Activation mechanisms of ATM/ATR are discussed in the article. Activated proteins signal the presence of DNA damage by phosphorylating targets involved in cell cycle arrest. ATM primarily regulates these phosphorylation events in response to IR (DSBs) and ATR controls it after exposure of cells to UV light and replication arrest (stalled forks). In addition to CHK1/CHK2 phosphorylation discussed in the article, ATM‐dependent phosphorylation of p53 on Ser‐15, which modulates the transactivation potential of p53, and of Mdm2 on Ser‐395, an E3 ligase that targets p53 for degradation, is also shown. Mdm2 phosphorylation inhibits the Mdm2–p53 interaction, leading to stabilisation of p53. Further, p21 is shown as downstream effector of p53, which inhibits the activity of Cdk2/Cyclin E/A.

Figure 3.

DNA repair genes maintain genomic stability. When cells lack functional repair proteins, they fail to repair DSBs correctly, leading to genomic instability and the accumulation of mutations. These events trigger cell cycle checkpoints, resulting in cell cycle arrest or death of affected cells. However, if the checkpoints are inactivated by mutations (e.g. p53), this can lead to tumourigenesis.

Figure 4.

Synthetic lethality occurs when inhibition of a single pathway or gene alone does not cause lethality but does so in combination with inhibition of another pathway or gene (e.g. the synthetically lethal combination of BRCA1 and PARP1 inhibition).



Bermudez VP, Lindsey‐Boltz LA, Cesare AJ et al. (2003) Loading of the human 9‐1‐1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17‐replication factor C complex in vitro. Proceedings of the National Academy of Sciences of the USA 100: 1633–1638.

Bunting SF, Callen E, Wong N et al. (2010) 53BP1 inhibits homologous recombination in Brca1‐deficient cells by blocking resection of DNA breaks. Cell 141: 243–254.

Chapman JR, Taylor MRG and Boulton SJ (2012) Playing the end game: DNA double‐strand break repair pathway choice. Molecular Cell 47: 497–510.

Charrier JD, Durrant SJ, Golec JM et al. (2011) Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. Journal of Medicinal Chemistry 54: 2320–2330.

Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nature Reviews Cancer 12: 801–817.

Davis AJ and Chen DJ (2013) DNA double strand break repair via non‐homologous end‐joining. Translational Cancer Research 2: 130–143.

Deans AJ and West SC (2011) DNA interstrand crosslink repair and cancer. Nature Reviews Cancer 11: 467–480.

De Summa S, Pinto R, Sambiasi D et al. (2013) BRCAness: a deeper insight into basal‐like breast tumors. Annals of Oncology 24(suppl. 8): viii13–viii21.

De Vos M, Schreiber V and Dantzer F (2012) The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochemical Pharmacology 84: 137–146.

Dupre A, Boyer‐Chatenet L, Sattler RM et al. (2008) A forward chemical genetic screen reveals an inhibitor of the Mre11‐Rad50‐Nbs1 complex. Nature Chemical Biology 4: 119–125.

Ellison V and Stillman B (2003) Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5′ recessed DNA. PLoS Biology 1.

Fackenthal JD and Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nature Reviews Cancer 7: 937–948.

Golding SE, Rosenberg E, Valerie N et al. (2009) Improved ATM kinase inhibitor KU‐60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Molecular Cancer Therapeutics 8: 2894–2902.

Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144: 646–674.

Helleday T (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Molecular Oncology 5: 387–393.

Hsieh P and Yamane K (2008) DNA mismatch repair: molecular mechanism, cancer, and ageing. Mechanisms of Ageing and Development 129: 391–407.

Iacovoni JS, Caron P, Lassadi I et al. (2010) High‐resolution profiling of gammaH2AX around DNA double strand breaks in the mammalian genome. EMBO Journal 29: 1446–1457.

Infante JR and Burris HA III (2013) PARP inhibitors: pitfalls and promises. Lancet Oncology 14: 798–799.

Jaspers JE, Kersbergen A, Boon U et al. (2013) Loss of 53BP1 causes PARP inhibitor resistance in Brca1‐mutated mouse mammary tumors. Cancer Discovery 3: 68–81.

Kim H and D'Andrea AD (2012) Regulation of DNA cross‐link repair by the Fanconi anemia/BRCA pathway. Genes and Development 26: 1393–1408.

Krejci L, Altmannova V, Spirek M and Zhao X (2012) Homologous recombination and its regulation. Nucleic Acids Research 40: 5795–5818.

Kruse JP and Gu W (2009) Modes of p53 regulation. Cell 137: 609–622.

Larsen JE and Minna JD (2011) Molecular biology of lung cancer: clinical implications. Clinics in Chest Medicine 32: 703–740.

Lukas J, Lukas C and Bartek J (2011) More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nature Cell Biology 13: 1161–1169.

Luo X and Kraus WL (2012) On PAR with PARP: cellular stress signaling through poly(ADP‐ribose) and PARP‐1. Genes and Development 26: 417–432.

Malumbres M and Barbacid M (2005) Mammalian cyclin‐dependent kinases. Trends in Biochemical Sciences 30: 630–641.

di Masi A and Antoccia A (2008) NBS1 heterozygosity and cancer risk. Current Genomics 9: 275–281.

Matsuoka S, Ballif BA, Smogorzewska A et al. (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316: 1160–1166.

Mortusewicz O, Fouquerel E, Ame JC, Leonhardt H and Schreiber V (2011) PARG is recruited to DNA damage sites through poly(ADP‐ribose)‐ and PCNA‐dependent mechanisms. Nucleic Acids Research 39: 5045–5056.

Moynahan ME and Jasin M (2010) Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nature Reviews Molecular Cell Biology 11: 196–207.

Muller PA and Vousden KH (2013) p53 mutations in cancer. Nature Cell Biology 15: 2–8.

Nakanishi M, Niida H, Murakami H and Shimada M (2009) DNA damage responses in skin biology – implications in tumor prevention and aging acceleration. Journal of Dermatological Science 56: 76–81.

Nam EA and Cortez D (2011) ATR signalling: more than meeting at the fork. Biochemical Journal 436: 527–536.

O'Driscoll M, Gennery AR, Seidel J, Concannon P and Jeggo PA (2004) An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS‐SCID and ATR‐Seckel syndrome. DNA Repair (AMST) 3: 1227–1235.

Olivier M, Hollstein M and Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harbor Perspectives in Biology 2: a001008.

Pierce AJ, Hu P, Han M, Ellis N and Jasin M (2001) Ku DNA end‐binding protein modulates homologous repair of double‐strand breaks in mammalian cells. Genes and Development 15: 3237–3242.

Polo SE and Jackson SP (2011) Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes and Development 25: 409–433.

Reaper PM, Griffiths MR, Long JM et al. (2011) Selective killing of ATM‐ or p53‐deficient cancer cells through inhibition of ATR. Nature Chemical Biology 7: 428–430.

Riley T, Sontag E, Chen P and Levine A (2008) Transcriptional control of human p53‐regulated genes. Nature Reviews Molecular Cell Biology 9: 402–412.

Robertson AB, Klungland A, Rognes T and Leiros I (2009) DNA repair in mammalian cells: base excision repair: the long and short of it. Cellular and Molecular Life Sciences 66: 981–993.

Sandhu SK, Schelman WR, Wilding G et al. (2013) The poly(ADP‐ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose‐escalation trial. Lancet Oncology 14: 882–892.

Shiloh Y and Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Reviews Molecular Cell Biology 14: 197–210.

Smith J, Tho LM, Xu N and Gillespie DA (2010) The ATM‐Chk2 and ATR‐Chk1 pathways in DNA damage signaling and cancer. Advances in Cancer Research 108: 73–112.

Srivastava M, Nambiar M, Sharma S et al. (2012) An inhibitor of nonhomologous end‐joining abrogates double‐strand break repair and impedes cancer progression. Cell 151: 1474–1487.

Symington LS and Gautier J (2011) Double‐strand break end resection and repair pathway choice. Annual Review of Genetics 45: 247–271.

Thompson D, Duedal S, Kirner J et al. (2005) Cancer risks and mortality in heterozygous ATM mutation carriers. Journal of the National Cancer Institute 97: 813–822.

Thompson LH (2012) Recognition, signaling, and repair of DNA double‐strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography. Mutation Research 751: 158–246.

Wang S‐J and Gu W (2014) To be, or not to be: functional dilemma of p53 metabolic regulation. Current Opinion in Oncology 26: 78–85.

Xu Y and Price BD (2011) Chromatin dynamics and the repair of DNA double strand breaks. Cell Cycle 10: 261–267.

Zimmermann M and de Lange T (2013) 53BP1: pro choice in DNA repair. Trends in Cell Biology 24: 108–117.

Further Reading

Adamson B, Smogorzewska A, Sigoillot FD, King RW and Elledge SJ (2012) A genome‐wide homologous recombination screen identifies the RNA‐binding protein RBMX as a component of the DNA‐damage response. Nature Cell Biology 14: 318–328.

Beli P, Lukashchuk N, Wagner SA et al. (2012) Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response. Molecular Cell 46: 212–225.

Bhatti S, Kozlov S, Farooqi AA et al. (2011) ATM protein kinase: the linchpin of cellular defenses to stress. Cellular and Molecular Life Sciences: CMLS 68: 2977–3006.

Ciccia A and Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Molecular Cell 40: 179–204.

Cimprich KA and Cortez D (2008) ATR: an essential regulator of genome integrity. Nature Reviews Molecular Cell Biology 9: 616–627.

Goodarzi AA and Jeggo PA (2013) The repair and signaling responses to DNA double‐strand breaks. Advances in Genetics 82: 1–45.

Khanna KK and Jackson SP (2001) DNA double‐strand breaks: signaling, repair and the cancer connection. Nature Genetics 27: 247–254.

Liu S, Shiotani B, Lahiri M et al. (2011) ATR autophosphorylation as a molecular switch for checkpoint activation. Molecular Cell 43: 192–202.

McKinnon PJ (2012) ATM and the molecular pathogenesis of ataxia telangiectasia. Annual Review of Pathology 7: 303–321.

Web Links

Clinical Trials. www.clinicaltrials.gov

COSMIC: Catalogue of Somatic Mutations in Cancer. cancer.sanger.ac.uk/cancergenome/projects/cosmic

Online Mendelian Inheritance in Man Catalogue of Human Genes and Genetic Disorders. www.omim.org

The American Association for Cancer Research Cancer Progress Report. cancerprogressreport.org

The National Institute of Cancer Drug Dictionary. http://www.cancer.gov/drugdictionary

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bain, Amanda L, Mastrocola, Adam S, Tibbetts, Randal S, and Khanna, Kum Kum(Apr 2014) DNA Damage Response: From Tumourigenesis to Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006107.pub2]