Skip to main content
SpringerLink
Log in

The DNA Damage Response: Roles in Cancer Etiology and Treatment

  • Chapter
  • First Online:
Targeting the DNA Damage Response for Anti-Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Cancer is one of the highest causes of morbidity and mortality worldwide. Traditional chemotherapeutics are associated with toxic side effects due to a lack of specificity for cancer cells. A new and rapidly expanding class of drugs known as targeted therapeutics are being developed that have high therapeutic potential with less severe side effects in comparison to conventional chemotherapeutics. Targeted therapeutics are aimed at defects found in cancer cells that are not present in the highly-proliferative cells of normal tissues. These defects include dys regulated oncogenes and DNA repair defects that cause cells to rely heavily on the DNA damage response (DDR) and checkpoint signaling. This association indicates that the DDR may include promising targets for targeted therapeutics. Examples of such therapeutics currently under investigation and in clinical use are described here, including inhibitors of PARP, DNA-PKcs and the ATR-CHK1 signaling pathway. Targeted therapeutics not only offer the promise of killing cancers with reduced side effects, but are well suited to use in combination with other therapeutics to increase efficacy and kill cancers before drug-resistance can occur.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • American Cancer Society 2014 Second cancers in adults. 12/11/14 [cited 2016 11/14/16]; Available from: http://www.cancer.org/acs/groups/cid/documents/webcontent/002043-pdf.pdf

  • An X et al (2010) BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res 34(10):1255–1268

    Article  PubMed  CAS  Google Scholar 

  • Andreassen PR, D'Andrea AD, Taniguchi T (2004) ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 18(16):1958–1963

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Anglian Breast Cancer Study Group (2000) Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer 83(10):1301–1308

    Article  PubMed Central  Google Scholar 

  • Atherton-Fessler S et al (1994) Cell cycle regulation of the p34cdc2 inhibitory kinases. Mol Biol Cell 5(9):989–1001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Audeh MW et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376(9737):245–251

    Article  PubMed  CAS  Google Scholar 

  • Bartkova J et al (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434(7035):864–870

    Article  PubMed  CAS  Google Scholar 

  • Bartkova J et al (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444(7119):633–637

    Article  PubMed  CAS  Google Scholar 

  • Baumann P, West SC (1998) Role of the human RAD51 protein in homologous recombination and double-stranded-break repair. Trends Biochem Sci 23(7):247–251

    Article  PubMed  CAS  Google Scholar 

  • Beck H et al (2012) Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol Cell Biol 32(20):4226–4236

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bester AC et al (2011) Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145(3):435–446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bignell GR et al (2010) Signatures of mutation and selection in the cancer genome. Nature 463(7283):893–898

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Booher RN, Holman PS, Fattaey A (1997) Human Myt1 is a cell cycle-regulated kinase that inhibits Cdc2 but not Cdk2 activity. J Biol Chem 272(35):22300–22306

    Article  PubMed  CAS  Google Scholar 

  • Bouwman P et al (2010) 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol 17(6):688–695

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boyer AS et al (2013) The human specialized DNA polymerases and non-B DNA: vital relationships to preserve genome integrity. J Mol Biol 425(23):4767–4781

    Article  PubMed  CAS  Google Scholar 

  • Branzei D, Foiani M (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9(4):297–308

    Article  PubMed  CAS  Google Scholar 

  • Branzei D, Foiani M (2010) Maintaining genome stability at the replication fork. Nat Rev Mol Cell Biol 11(3):208–219

    Article  PubMed  CAS  Google Scholar 

  • Brown EJ, Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14(4):397–402

    PubMed  PubMed Central  CAS  Google Scholar 

  • Brown EJ, Baltimore D (2003) Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev 17(5):615–628

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bryant HE et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917

    Article  PubMed  CAS  Google Scholar 

  • Bunting SF et al (2010) 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141(2):243–254

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474(7353):609–615

    Article  CAS  Google Scholar 

  • Casper AM et al (2002) ATR regulates fragile site stability. Cell 111(6):779–789

    Article  PubMed  CAS  Google Scholar 

  • Chang HHY et al (2017) Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol 18(8):495–506

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chanoux RA et al (2009) ATR and H2AX cooperate in maintaining genome stability under replication stress. J Biol Chem 284(9):5994–6003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen MS, Ryan CE, Piwnica-Worms H (2003) Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding. Mol Cell Biol 23(21):7488–7497

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen L et al (2008) Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J Biol Chem 283(12):7713–7720

    Article  PubMed  CAS  Google Scholar 

  • Chiarugi A (2012) A snapshot of chemoresistance to PARP inhibitors. Trends Pharmacol Sci 33(1):42–48

    Article  PubMed  CAS  Google Scholar 

  • Cortez D (2015) Preventing replication fork collapse to maintain genome integrity. DNA Repair (Amst) 32:149–157

    Article  CAS  Google Scholar 

  • Couch FB et al (2013) ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev 27(14):1610–1623

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Couedel C et al (2004) Collaboration of homologous recombination and nonhomologous end-joining factors for the survival and integrity of mice and cells. Genes Dev 18(11):1293–1304

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Curtis RE, Freedman DM, Ron E, LAG R, Hacker DG, Edwards BK, Tucker MA, Fraumeni JF Jr (2006) New malignancies among cancer survivors: SEER cancer registries, 1973–2000. NIH: National Cancer Institute, Bethesda, MD

    Google Scholar 

  • Denko NC et al (1994) The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle. Proc Natl Acad Sci U S A 91(11):5124–5128

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Di Micco R et al (2006) Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444(7119):638–642

    Article  PubMed  CAS  Google Scholar 

  • Dillon LW, Burrow AA, Wang YH (2010) DNA instability at chromosomal fragile sites in cancer. Curr Genomics 11(5):326–337

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dominguez-Kelly R et al (2011) Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. J Cell Biol 194(4):567–579

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Duda H et al (2016) A mechanism for controlled breakage of under-replicated chromosomes during mitosis. Dev Cell 39(6):740–755

    Article  PubMed  CAS  Google Scholar 

  • Falck J et al (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410(6830):842–847

    Article  PubMed  CAS  Google Scholar 

  • Farmer H et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921

    Article  PubMed  CAS  Google Scholar 

  • Feijoo C et al (2001) Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. J Cell Biol 154(5):913–923

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Felsher DW, Bishop JM (1999) Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc Natl Acad Sci U S A 96(7):3940–3944

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fernandez-Medarde A, Santos E (2011) Ras in cancer and developmental diseases. Genes Cancer 2(3):344–358

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ferrao PT et al (2012) Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells. Oncogene 31(13):1661–1672

    Article  PubMed  CAS  Google Scholar 

  • Flaherty KT et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fokas E et al (2012) Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis 3:e441

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gilad O et al (2010) Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res 70(23):9693–9702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Glover TW et al (1984) DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 67(2):136–142

    Article  PubMed  CAS  Google Scholar 

  • Gong Z et al (2010) BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Mol Cell 37(3):438–446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gorgoulis VG et al (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434(7035):907–913

    Article  PubMed  CAS  Google Scholar 

  • Gottlieb TM, Jackson SP (1993) The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72(1):131–142

    Article  PubMed  CAS  Google Scholar 

  • Graham TG, Walter JC, Loparo JJ (2016) Two-stage synapsis of DNA ends during non-homologous end joining. Mol Cell 61(6):850–858

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gumy-Pause F, Wacker P, Sappino AP (2004) ATM gene and lymphoid malignancies. Leukemia 18(2):238–242

    Article  PubMed  CAS  Google Scholar 

  • Gurley KE, Kemp CJ (2001) Synthetic lethality between mutation in Atm and DNA-PK(cs) during murine embryogenesis. Curr Biol 11(3):191–194

    Article  PubMed  CAS  Google Scholar 

  • Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319(5868):1352–1355

    Article  PubMed  CAS  Google Scholar 

  • Harper JW et al (1995) Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 6(4):387–400

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hollstein M et al (1991) p53 mutations in human cancers. Science 253(5015):49–53

    Article  CAS  PubMed  Google Scholar 

  • Hurley LH (2002) DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer 2(3):188–200

    Article  PubMed  CAS  Google Scholar 

  • Ishiai M et al (2008) FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol 15(11):1138–1146

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kakarougkas A, Jeggo PA (2014) DNA DSB repair pathway choice: an orchestrated handover mechanism. Br J Radiol 87(1035):20130685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432(7015):316–323

    Article  PubMed  CAS  Google Scholar 

  • Kim H et al (2016) Targeting the ATR/CHK1 Axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian cancer models. Clin Cancer Res 23(12):3097–3108

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kiraz Y et al (2016) Major apoptotic mechanisms and genes involved in apoptosis. Tumour Biol 37(7):8471–8486

    Article  PubMed  CAS  Google Scholar 

  • Kolas NK et al (2007) Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318(5856):1637–1640

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Krajewska M et al (2015) ATR inhibition preferentially targets homologous recombination-deficient tumor cells. Oncogene 34(26):3474–3481

    Article  PubMed  CAS  Google Scholar 

  • Kwak EL et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lavin MF (2007) ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks. Oncogene 26(56):7749–7758

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Kumagai A, Dunphy WG (2001) Positive regulation of Wee1 by Chk1 and 14-3-3 proteins. Mol Biol Cell 12(3):551–563

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Leung M et al (2011) Poly(ADP-ribose) polymerase-1 inhibition: preclinical and clinical development of synthetic lethality. Mol Med 17(7–8):854–862

    PubMed  PubMed Central  CAS  Google Scholar 

  • Li J, Stern DF (2005) Regulation of CHK2 by DNA-dependent protein kinase. J Biol Chem 280(12):12041–12050

    Article  PubMed  CAS  Google Scholar 

  • Litman R et al (2005) BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8(3):255–265

    Article  PubMed  CAS  Google Scholar 

  • Liu Q et al (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev 14(12):1448–1459

    PubMed  PubMed Central  CAS  Google Scholar 

  • Lord CJ, Ashworth A (2016) BRCAness revisited. Nat Rev Cancer 16(2):110–120

    Article  PubMed  CAS  Google Scholar 

  • Ma Y et al (2002) Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108(6):781–794

    Article  PubMed  CAS  Google Scholar 

  • Mailand N et al (2000) Rapid destruction of human Cdc25A in response to DNA damage. Science 288(5470):1425–1429

    Article  PubMed  CAS  Google Scholar 

  • Mailand N et al (2007) RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131(5):887–900

    Article  PubMed  CAS  Google Scholar 

  • Malkin D et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(4985):1233–1238

    Article  PubMed  CAS  Google Scholar 

  • Malone KE et al (2006) Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 66(16):8297–8308

    Article  PubMed  CAS  Google Scholar 

  • Marsit CJ et al (2004) Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene 23(4):1000–1004

    Article  PubMed  CAS  Google Scholar 

  • Matos J, West SC (2014) Holliday junction resolution: regulation in space and time. DNA Repair (Amst) 19:176–181

    Article  CAS  Google Scholar 

  • Matsuoka S et al (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316(5828):1160–1166

    Article  PubMed  CAS  Google Scholar 

  • Mazin AV et al (2010) Rad54, the motor of homologous recombination. DNA Repair (Amst) 9(3):286–302

    Article  CAS  Google Scholar 

  • Mendes-Pereira AM et al (2009) Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med 1(6–7):315–322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Merrick CJ, Jackson D, Diffley JF (2004) Visualization of altered replication dynamics after DNA damage in human cells. J Biol Chem 279(19):20067–20075

    Article  PubMed  CAS  Google Scholar 

  • Mohni KN et al (2015) A synthetic lethal screen identifies DNA repair pathways that sensitize cancer cells to combined ATR inhibition and cisplatin treatments. PLoS One 10(5):e0125482

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mueller PR et al (1995) Myt1: a membrane-associated inhibitory kinase that phosphorylates Cdc2 on both threonine-14 and tyrosine-15. Science 270(5233):86–90

    Article  PubMed  CAS  Google Scholar 

  • Murai J et al (2012) Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 72(21):5588–5599

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Murga M et al (2011) Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol 18(12):1331–1335

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • NIH 2015 National cancer institite–side effects. 04/29/15 [cited 2016 11/14/16]; Available from: https://www.cancer.gov/about-cancer/treatment/side-effects

  • Nilsson JA, Cleveland JL (2003) Myc pathways provoking cell suicide and cancer. Oncogene 22(56):9007–9021

    Article  PubMed  CAS  Google Scholar 

  • Norbury C, Blow J, Nurse P (1991) Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J 10(11):3321–3329

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Parker LL, Piwnica-Worms H (1992) Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science 257(5078):1955–1957

    Article  PubMed  CAS  Google Scholar 

  • Patel AG, Sarkaria JN, Kaufmann SH (2011) Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A 108(8):3406–3411

    Article  PubMed  PubMed Central  Google Scholar 

  • Prevo R et al (2012) The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther 13(11):1072–1081

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ragland RL et al (2013) RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. Genes Dev 27(20):2259–2273

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reaper PM et al (2011) Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 7(7):428–430

    Article  PubMed  CAS  Google Scholar 

  • Regal JA et al (2013) Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms. Hum Mol Genet 22(25):5146–5159

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Riabinska A et al (2013) Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci Transl Med 5(189):189ra78

    Article  PubMed  CAS  Google Scholar 

  • Rogakou EP et al (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273(10):5858–5868

    Article  PubMed  CAS  Google Scholar 

  • Santocanale C, Diffley JF (1998) A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature 395(6702):615–618

    Article  PubMed  CAS  Google Scholar 

  • Schoppy DW et al (2012) Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest 122(1):241–252

    Article  PubMed  CAS  Google Scholar 

  • Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14(4):197–210

    Article  PubMed  CAS  Google Scholar 

  • Siddick ZH (2002) The cancer handbook. In: Mechanisms of action of cancerchemotherapeutic agents: DNA-interactive alkylating agents and antitumour platinum-based drugs, 1st edn. John Wiley & Sons, Ltd, Hoboken, New Jersey

    Google Scholar 

  • Sorensen CS et al (2003) Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell 3(3):247–258

    Article  PubMed  CAS  Google Scholar 

  • Sorensen CS et al (2005) The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol 7(2):195–201

    Article  PubMed  CAS  Google Scholar 

  • Sosman JA et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366(8):707–714

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stewart GS et al (2003) MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421(6926):961–966

    Article  PubMed  CAS  Google Scholar 

  • Stiff T et al (2004) ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 64(7):2390–2396

    Article  PubMed  CAS  Google Scholar 

  • Strausfeld U et al (1991) Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 protein. Nature 351(6323):242–245

    Article  PubMed  CAS  Google Scholar 

  • Sy SM, Huen MS, Chen J (2009) PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci U S A 106(17):7155–7160

    Article  PubMed  PubMed Central  Google Scholar 

  • Toledo LI et al (2011) A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 18(6):721–727

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Toledo LI et al (2013) ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155(5):1088–1103

    Article  PubMed  CAS  Google Scholar 

  • Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4(10):814–819

    Article  PubMed  CAS  Google Scholar 

  • Varon R et al (2001) Mutations in the nijmegen breakage syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res 61(9):3570–3572

    PubMed  CAS  Google Scholar 

  • Vita M, Henriksson M (2006) The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 16(4):318–330

    Article  PubMed  CAS  Google Scholar 

  • Waddell N et al (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540):495–501

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Waters LS et al (2009) Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance. Microbiol Mol Biol Rev 73(1):134–154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Welburn JP et al (2007) How tyrosine 15 phosphorylation inhibits the activity of cyclin-dependent kinase 2-cyclin A. J Biol Chem 282(5):3173–3181

    Article  PubMed  CAS  Google Scholar 

  • Williams JS, Lujan SA, Kunkel TA (2016) Processing ribonucleotides incorporated during eukaryotic DNA replication. Nat Rev Mol Cell Biol 17(6):350–363

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wyatt HD et al (2013) Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. Mol Cell 52(2):234–247

    Article  PubMed  CAS  Google Scholar 

  • Xia B et al (2006) Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 22(6):719–729

    Article  PubMed  CAS  Google Scholar 

  • Yazinski SA et al (2017) ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev 31(3):318–332

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zamborszky J et al (2017) Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions. Oncogene 36(6):746–755

    Article  PubMed  CAS  Google Scholar 

  • Zeman MK, Cimprich KA (2014) Causes and consequences of replication stress. Nat Cell Biol 16(1):2–9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao H, Watkins JL, Piwnica-Worms H (2002) Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc Natl Acad Sci U S A 99(23):14795–14800

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300(5625):1542–1548

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank our support from the National Cancer Institute of the National Institutes of Health under award numbers: R41CA203436 (LB, OG, EJB) and 1R01CA189743 (EJB). Additional funding was provided through the Ben Franklin Technology Partners of Southeastern PA, an initiative of the Pennsylvania Department of Community and Economic Development funded by the Ben Franklin Technology Development Authority (LB, OG), the Pennsylvania Department of Health (EJB), The Basser Center for BRCA Research (EJB), and the Abramson Family Cancer Research Institute (EJB).

Author information

Authors and Affiliations

  1. Atrin Pharmaceuticals, Pennsylvania Biotechnology Center, Doylestown, PA, USA

    Laura R. Butler & Oren Gilad

  2. Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Eric J. Brown

Authors
  1. Laura R. Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oren Gilad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric J. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric J. Brown .

Editor information

Editors and Affiliations

  1. Vertex Pharmaceuticals (Europe) Ltd, Abingdon, Oxfordshire, United Kingdom

    John Pollard

  2. Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola Curtin

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Butler, L.R., Gilad, O., Brown, E.J. (2018). The DNA Damage Response: Roles in Cancer Etiology and Treatment. In: Pollard, J., Curtin, N. (eds) Targeting the DNA Damage Response for Anti-Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-75836-7_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-75836-7_2

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-75834-3

  • Online ISBN: 978-3-319-75836-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation