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DNA helicases involved in DNA repair and their roles in cancer

Nature Reviews Cancer volume 13, pages 542–558 (2013)Cite this article

Subjects

Key Points

  • Helicase-dependent DNA damage response and repair mechanisms help cells to cope with endogenous or exogenous stress to prevent chromosomal instability and maintain cellular homeostasis.

  • Inactivating mutations in DNA helicase genes are linked to genetic disorders that are frequently associated with various cancers. However, the expression of many DNA helicases is upregulated in transformed or neoplastic cells and tissues and is required for cancer cell proliferation or resistance to DNA damage imposed by chemotherapies.

  • The RecQ and iron-sulphur (Fe-S) families of DNA helicases have prominent roles in the maintenance of genomic stability through their catalytic functions and protein interactions in telomere maintenance and DNA repair pathways including nucleotide-excision repair (NER), homologous recombination (HR)-mediated repair of double-strand breaks (DSBs), interstrand crosslink (ICL) repair, and base-excision repair (BER).

  • Specialized DNA helicases efficiently unwind G-quadruplex (G4) DNA and other forms of alternative DNA structures such as telomeric displacement loops (T-loops). Emerging evidence suggests that DNA helicases that unwind non-conventional DNA structures have important roles in the replication or repair of telomeres.

  • Replication forks in rapidly dividing cancer cells are likely to encounter DNA lesions that perturb fork progression. Evidence suggests that certain DNA helicases help cells to cope with replicative lesions by remodelling the fork, restoring the integrity of broken replication forks, or having a role in the signalling mechanism for the intra-S-phase checkpoint.

  • Elevated expression of DNA helicases in rapidly proliferating cells and tumours suggests that they have a role in resistance to DNA-damaging agents and may represent good biomarkers for response to chemotherapies.

  • High-throughput screening of chemical libraries may prove to be beneficial for the discovery of small molecules that modulate helicase function in vivo. Such compounds may be useful in synthetic lethal approaches used in anticancer strategies that target tumours with existing DNA repair deficiencies.

Abstract

Helicases have major roles in genome maintenance by unwinding structured nucleic acids. Their prominence is marked by various cancers and genetic disorders that are linked to helicase defects. Although considerable effort has been made to understand the functions of DNA helicases that are important for genomic stability and cellular homeostasis, the complexity of the DNA damage response leaves us with unanswered questions regarding how helicase-dependent DNA repair pathways are regulated and coordinated with cell cycle checkpoints. Further studies may open the door to targeting helicases in order to improve cancer treatments based on DNA-damaging chemotherapy or radiation.

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Figure 1: Molecular functions of DNA helicases.
Figure 2: Involvement of helicases in nucleotide excision and interstrand crosslink DNA repair mechanisms.
Figure 3: Involvement of helicases in homologous recombination and base excision DNA repair mechanisms.
Figure 4: Roles of DNA helicases during replication stress.
Figure 5: Helicase functions at telomeres and potential for anticancer therapy.

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References

  1. Singleton, M. R., Dillingham, M. S. & Wigley, D. B. Structure and mechanism of helicases and nucleic acid translocases. Annu. Rev. Biochem. 76, 23–50 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Umate, P., Tuteja, N. & Tuteja, R. Genome-wide comprehensive analysis of human helicases. Commun. Integr. Biol. 4, 118–137 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Abdel-Monem, M. & Hoffmann-Berling, H. Enzymic unwinding of DNA. 1. Purification and characterization of a DNA-dependent ATPase from Escherichia coli. Eur. J. Biochem. 65, 431–440 (1976).

    Article  CAS  PubMed  Google Scholar 

  4. Suhasini, A. N. & Brosh, R. M. Jr. Disease-causing missense mutations in human DNA helicase disorders. Mutat. Res. 752, 138–152 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Futami, K., Ogasawara, S., Goto, H., Yano, H. & Furuichi, Y. RecQL1 DNA repair helicase: a potential tumor marker and therapeutic target against hepatocellular carcinoma. Int. J. Mol. Med. 25, 537–545 (2010).

    CAS  PubMed  Google Scholar 

  6. Kawabe, T. et al. Differential regulation of human RecQ family helicases in cell transformation and cell cycle. Oncogene 19, 4764–4772 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Su, Y. et al. Human RecQL4 helicase plays critical roles in prostate carcinogenesis. Cancer Res. 70, 9207–9217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Turley, H., Wu, L., Canamero, M., Gatter, K. C. & Hickson, I. D. The distribution and expression of the Bloom's syndrome gene product in normal and neoplastic human cells. Br. J. Cancer 85, 261–265 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chu, W. K. & Hickson, I. D. RecQ helicases: multifunctional genome caretakers. Nature Rev. Cancer 9, 644–654 (2009).

    Article  CAS  Google Scholar 

  10. Monnat, R. J. Jr. Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology. Semin. Cancer Biol. 20, 329–339 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ellis, N. A. et al. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83, 655–666 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Yu, C. E. et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 (1996). References 11 and 12 represent seminal discoveries in the helicase field: the discoveries of the predicted DNA helicase genes that are genetically linked to the cancer predisposition disorders Bloom syndrome and Werner syndrome, the latter of which is characterized by premature ageing.

    Article  CAS  PubMed  Google Scholar 

  13. Kitao, S. et al. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nature Genet. 22, 82–84 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Siitonen, H. A. et al. Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. Hum. Mol. Genet. 12, 2837–2844 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Van Maldergem, L. et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J. Med. Genet. 43, 148–152 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Lauper, J. M., Krause, A., Vaughan, T. L. & Monnat, R. J. Jr. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS ONE 8, e59709 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Siitonen, H. A. et al. The mutation spectrum in RECQL4 diseases. Eur. J. Hum. Genet. 17, 151–158 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Li, D. et al. Single nucleotide polymorphisms of RecQ1, RAD54L and ATM genes are associated with reduced survival of pancreatic cancer. J. Clin. Oncol. 24, 1720–1728 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Li, D. et al. Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival. Cancer Res. 66, 3323–3330 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sharma, S. et al. RECQL, a member of the RecQ family of DNA helicases, suppresses chromosomal instability. Mol. Cell. Biol. 27, 1784–1794 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sharma, S. & Brosh, R. M. Jr. Human RECQ1 Is a DNA damage responsive protein required for genotoxic stress resistance and suppression of sister chromatid exchanges. PLoS ONE 2, e1297 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Parvathaneni, S. et al. Human RECQ1 interacts with Ku70/80 and modulates end-joining of double-strand breaks. PLoS ONE 8, e62481 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sharma, S., Phatak, P., Stortchevoi, A., Jasin, M. & Larocque, J. R. RECQ1 plays a distinct role in cellular response to oxidative DNA damage. DNA Repair 11, 537–549 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Popuri, V., Croteau, D. L., Brosh, R. M. Jr. & Bohr, V. A. RECQ1 is required for cellular resistance to replication stress and catalyzes strand exchange on stalled replication fork structures. Cell Cycle 11, 4252–4265 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Arai, A. et al. RECQL1 and WRN proteins are potential therapeutic targets in head and neck squamous cell carcinoma. Cancer Res. 71, 4598–4607 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Futami, K. et al. Induction of mitotic cell death in cancer cells by small interference RNA suppressing the expression of RecQL1 helicase. Cancer Sci. 99, 71–80 (2008).

    CAS  PubMed  Google Scholar 

  27. Futami, K. et al. Anticancer activity of RecQL1 helicase siRNA in mouse xenograft models. Cancer Sci. 99, 1227–1236 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Mendoza-Maldonado, R. et al. The human RECQ1 helicase is highly expressed in glioblastoma and plays an important role in tumor cell proliferation. Mol. Cancer 10, 83 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ramamoorthy, M. et al. RECQL5 cooperates with topoisomerase IIα in DNA decatenation and cell cycle progression. Nucleic Acids Res. 40, 1621–1635 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Hu, Y. et al. RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments. Genes Dev. 21, 3073–3084 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Islam, M. N. et al. RecQL5 promotes genome stabilization through two parallel mechanisms—interacting with RNA polymerase II and acting as a helicase. Mol. Cell. Biol. 30, 2460–2472 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tadokoro, T. et al. Human RECQL5 participates in the removal of endogenous DNA damage. Mol. Biol. Cell 23, 4273–4285 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wu, Y. & Brosh, R. M. Jr. DNA helicase and helicase-nuclease enzymes with a conserved iron-sulfur cluster. Nucleic Acids Res. 40, 4247–4260 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Digiovanna, J. J. & Kraemer, K. H. Shining a light on xeroderma pigmentosum. J. Invest. Dermatol. 132, 785–796 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Levitus, M. et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nature Genet. 37, 934–935 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Levran, O. et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nature Genet. 37, 931–933 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Capo-chichi, J.-M. et al. Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome. Hum. Mut. 34, 103–107 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. van der, L. P. et al. Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am. J. Hum. Genet. 86, 262–266 (2010).

    Article  CAS  Google Scholar 

  40. Ballew, B. J. et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in dyskeratosis congenita. Hum. Genet. 132, 473–480 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Le Guen, T. et al. Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability. Hum. Mol. Genet. 15 Apr 2013 (doi:10.1093/hmg/ddt178).

  42. Walne, A. J., Vulliamy, T., Kirwan, M., Plagnol, V. & Dokal, I. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am. J. Hum. Genet. 92, 448–453 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Flejter, W. L., McDaniel, L. D., Askari, M., Friedberg, E. C. & Schultz, R. A. Characterization of a complex chromosomal rearrangement maps the locus for in vitro complementation of xeroderma pigmentosum group D to human chromosome band 19q13. Genes Chromosomes Cancer 5, 335–342 (1992).

    Article  CAS  PubMed  Google Scholar 

  44. Flejter, W. L., McDaniel, L. D., Johns, D., Friedberg, E. C. & Schultz, R. A. Correction of xeroderma pigmentosum complementation group D mutant cell phenotypes by chromosome and gene transfer: involvement of the human ERCC2 DNA repair gene. Proc. Natl Acad. Sci. USA 89, 261–265 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kee, Y. & D'Andrea, A. D. Molecular pathogenesis and clinical management of Fanconi anemia. J. Clin. Invest. 122, 3799–3806 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cantor, S. B. & Guillemette, S. Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1. Future Oncol. 7, 253–261 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Uringa, E. J. et al. RTEL1 contributes to DNA replication and repair and telomere maintenance. Mol. Biol. Cell 23, 2782–2792 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vannier, J. B., Pavicic-Kaltenbrunner, V., Petalcorin, M. I., Ding, H. & Boulton, S. J. RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149, 795–806 (2012). This work shows that the RTEL1 helicase has a crucial role in telomere maintenance by disassembling T-loops and counteracting telomeric G-quadruplexes, which potentially impede replication or DNA repair and pose a source of telomere instability.

    Article  CAS  PubMed  Google Scholar 

  49. Barber, L. J. et al. RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135, 261–271 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Egan, K. M. et al. Cancer susceptibility variants and the risk of adult glioma in a US case-control study. J. Neurooncol. 104, 535–542 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nature Genet. 41, 899–904 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Wrensch, M. et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nature Genet. 41, 905–908 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Weeda, G. et al. Molecular cloning and biological characterization of the human excision repair gene ERCC-3. Mol. Cell. Biol. 10, 2570–2581 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Weeda, G. et al. A presumed DNA helicase encoded by ERCC-3 is involved in the human repair disorders xeroderma pigmentosum and Cockayne's syndrome. Cell 62, 777–791 (1990).

    Article  CAS  PubMed  Google Scholar 

  55. Gagou, M. E. et al. Suppression of apoptosis by PIF1 helicase in human tumor cells. Cancer Res. 71, 4998–5008 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Chisholm, K. M. et al. A genomewide screen for suppressors of Alu-mediated rearrangements reveals a role for PIF1. PLoS ONE 7, e30748 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Alzu, A. et al. Senataxin associates with replication forks to protect fork integrity across RNA-Polymerase-II-transcribed genes. Cell 151, 835–846 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yuce-Petronczki, O. & West, S. C. Senataxin, defective in the neurogenerative disorder AOA-2, lies at the interface of transcription and the DNA damage response. Mol. Cell Biol. 33, 406–417 (2012).

    Article  CAS  Google Scholar 

  59. Kang, Y. H., Lee, C. H. & Seo, Y. S. Dna2 on the road to Okazaki fragment processing and genome stability in eukaryotes. Crit. Rev. Biochem. Mol. Biol. 45, 71–96 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Duxin, J. P. et al. Human Dna2 is a nuclear and mitochondrial DNA maintenance protein. Mol. Cell. Biol. 29, 4274–4282 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nimonkar, A. V. et al. BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev. 25, 350–362 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zheng, L. et al. Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates. Mol. Cell 32, 325–336 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Copeland, W. C. Defects in mitochondrial DNA replication and human disease. Crit. Rev. Biochem. Mol. Biol. 47, 64–74 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brosh, R. M. Jr., Waheed, J. & Sommers, J. A. Biochemical characterization of the DNA substrate specificity of Werner syndrome helicase. J. Biol. Chem. 277, 23236–23245 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Suhasini, A. N. & Brosh, R. M. Jr. Mechanistic and biological aspects of helicase action on damaged DNA. Cell Cycle 9, 2317–2329 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Sontz, P. A., Mui, T. P., Fuss, J. O., Tainer, J. A. & Barton, J. K. DNA charge transport as a first step in coordinating the detection of lesions by repair proteins. Proc. Natl Acad. Sci. USA 109, 1856–1861 (2012). This study elegantly describes how DNA damage can be efficiently recognized by collaboration between DNA repair proteins that are able to carry out DNA charge transport.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Suhasini, A. N. et al. FANCJ helicase uniquely senses oxidative base damage in either strand of duplex DNA and is stimulated by replication protein A to unwind the damaged DNA substrate in a strand-specific manner. J. Biol. Chem. 284, 18458–18470 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ghosh, A., Rossi, M. L., Aulds, J., Croteau, D. & Bohr, V. A. Telomeric D-loops containing 8-oxo-2′-deoxyguanosine are preferred substrates for Werner and Bloom syndrome helicases and are bound by POT1. J. Biol. Chem. 284, 31074–31084 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Indiani, C. & O'Donnell, M. A. Proposal: source of single strand DNA that elicits the SOS response. Front. Biosci. 18, 312–323 (2013).

    Article  CAS  Google Scholar 

  70. Honda, M., Park, J., Pugh, R. A., Ha, T. & Spies, M. Single-molecule analysis reveals differential effect of ssDNA-binding proteins on DNA translocation by XPD helicase. Mol. Cell 35, 694–703 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Reardon, J. T. & Sancar, A. Nucleotide excision repair. Prog. Nucleic Acid Res. Mol. Biol. 79, 183–235 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Egly, J. M. & Coin, F. A history of TFIIH: Two decades of molecular biology on a pivotal transcription/repair factor. DNA Repair 10, 714–721 (2011). This review by two leading experts provides an interesting discussion of the molecular functions of TFIIH and their relation to diseases that are characterized by defects in DNA repair and transcription.

    Article  CAS  PubMed  Google Scholar 

  73. Sugasawa, K., Akagi, J., Nishi, R., Iwai, S. & Hanaoka, F. Two-step recognition of DNA damage for mammalian nucleotide excision repair: directional binding of the XPC complex and DNA strand scanning. Mol. Cell 36, 642–653 (2009). This paper describes in a refined system the interlinked mechanism for the initial detection and verification steps of mammalian NER. These steps involve strand-specific DNA binding by XPC and 5′ to 3′ translocation by XPD to search for and authenticate the lesion.

    Article  CAS  PubMed  Google Scholar 

  74. Mathieu, N., Kaczmarek, N., Ruthemann, P., Luch, A., & Naegeli, H. DNA quality control by a lesion sensor pocket of the xeroderma pigmentosum group D helicase subunit of TFIIH. Curr. Biol. 23, 204–212 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Fuss, J. O. & Tainer, J. A. XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase. DNA Repair 10, 697–713 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Clarkson, S. G. & Wood, R. D. Polymorphisms in the human XPD (ERCC2) gene, DNA repair capacity and cancer susceptibility: an appraisal. DNA Repair 4, 1068–1074 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Deans, A. J. & West, S. C. DNA interstrand crosslink repair and cancer. Nature Rev. Cancer 11, 467–480 (2011).

    Article  CAS  Google Scholar 

  78. Garaycoechea, J. I. et al. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 489, 571–575 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Rosado, I. V., Langevin, F., Crossan, G. P., Takata, M. & Patel, K. J. Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway. Nature Struct. Mol. Biol. 18, 1432–1434 (2011).

    Article  CAS  Google Scholar 

  80. Adamo, A. et al. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol. Cell 39, 25–35 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Pace, P. et al. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science 329, 219–223 (2010). References 80 and 81 describe how the FA DNA repair pathway suppresses toxic NHEJ in the repair of DNA ICLs.

    Article  CAS  PubMed  Google Scholar 

  82. Meetei, A. R. et al. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nature Genet. 37, 958–963 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Singh, T. R. et al. MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM. Mol. Cell 37, 879–886 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Peng, M. et al. The FANCJ/MutLα interaction is required for correction of the cross-link response in FA-J cells. EMBO J. 26, 3238–3249 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Meetei, A. R. et al. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol. Cell. Biol. 23, 3417–3426 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Deans, A. J. & West, S. C. FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. Mol. Cell 36, 943–953 (2009). References 85 and 86 together demonstrate that FA and Bloom syndrome are linked by proteins that function in a common nuclear complex through protein interaction domains in FANCM that facilitate its role in ICL repair and the maintenance of genomic stability.

    Article  CAS  PubMed  Google Scholar 

  87. Larocque, J. R. et al. Interhomolog recombination and loss of heterozygosity in wild-type and Bloom syndrome helicase (BLM)-deficient mammalian cells. Proc. Natl Acad. Sci. USA 108, 11971–11976 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Luo, G. et al. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nature Genet. 26, 424–429 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Suhasini, A. N. et al. Interaction between the helicases genetically linked to Fanconi anemia Group J and Bloom's syndrome. EMBO J. 30, 692–705 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Suhasini, A. N. et al. Fanconi anemia Group J helicase and MRE11 nuclease interact to facilitate the DNA damage response. Mol. Cell. Biol. 33, 2212–2227 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cheng, W. H. et al. Collaboration of Werner syndrome protein and BRCA1 in cellular responses to DNA interstrand cross-links. Nucleic Acids Res. 34, 2751–2760 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cheng, W. H. et al. WRN Is required for ATM activation and the S-phase checkpoint in response to interstrand crosslink-induced DNA double strand breaks. Mol. Biol. Cell 19, 3923–3933 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pichierri, P., Ammazzalorso, F., Bignami, M. & Franchitto, A. The Werner syndrome protein: linking the replication checkpoint response to genome stability. Aging 3, 311–318 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Moldovan, G. L. et al. DNA polymerase POLN participates in cross-link repair and homologous recombination. Mol. Cell. Biol. 30, 1088–1096 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Ward, J. D. et al. Overlapping mechanisms promote postsynaptic RAD-51 filament disassembly during meiotic double-strand break repair. Mol. Cell 37, 259–272 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Tafel, A. A., Wu, L. & McHugh, P. J. Human HEL308 localizes to damaged replication forks and unwinds lagging strand structures. J. Biol. Chem. 286, 15832–15840 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chan, K. L., Palmai-Pallag, T., Ying, S. & Hickson, I. D. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nature Cell Biol. 11, 753–760 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Naim, V. & Rosselli, F. The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nature Cell Biol. 11, 761–768 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Bernstein, K. A., Gangloff, S. & Rothstein, R. The RecQ DNA helicases in DNA repair. Annu. Rev. Genet. 44, 393–417 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Schwendener, S. et al. Physical interaction of RECQ5 helicase with RAD51 facilitates its anti-recombinase activity. J. Biol. Chem. 285, 15739–15745 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nimonkar, A. V., Ozsoy, A. Z., Genschel, J., Modrich, P. & Kowalczykowski, S. C. Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair. Proc. Natl Acad. Sci. USA 105, 16906–16911 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Bugreev, D. V., Yu, X., Egelman, E. H. & Mazin, A. V. Novel pro- and anti-recombination activities of the Bloom's syndrome helicase. Genes Dev. 21, 3085–3094 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chapman, J. R., Taylor, M. R. & Boulton, S. J. Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell 47, 497–510 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Cooper, M. P. et al. Ku complex interacts with and stimulates the Werner protein. Genes Dev. 14, 907–912 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kusumoto, R. et al. Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing. Biochemistry 47, 7548–7556 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Sallmyr, A., Tomkinson, A. E. & Rassool, F. V. Up-regulation of WRN and DNA ligase IIIα in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks. Blood 112, 1413–1423 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chen, L. et al. WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair. Aging Cell 2, 191–199 (2003).

    Article  PubMed  Google Scholar 

  108. Perry, J. J. et al. WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. Nature Struct. Mol. Biol. 13, 414–422 (2006).

    Article  CAS  Google Scholar 

  109. Swanson, C., Saintigny, Y., Emond, M. J. & Monnat, R. J. Jr. The Werner syndrome protein has separable recombination and survival functions. DNA Repair 3, 475–482 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Kennedy, R. D. et al. Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J. Clin. Invest. 117, 1440–1449 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. von Kobbe, C. et al. Central role for the Werner syndrome protein/poly(ADP-ribose) polymerase 1 complex in the poly(ADP-ribosyl)ation pathway after DNA damage. Mol. Cell. Biol. 23, 8601–8613 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Woo, L. L., Futami, K., Shimamoto, A., Furuichi, Y. & Frank, K. M. The Rothmund-Thomson gene product RECQL4 localizes to the nucleolus in response to oxidative stress. Exp. Cell Res. 312, 3443–3457 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Lebel, M., Lavoie, J., Gaudreault, I., Bronsard, M. & Drouin, R. Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice. Am. J. Pathol. 162, 1559–1569 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rossi, M. L., Ghosh, A. K. & Bohr, V. A. Roles of Werner syndrome protein in protection of genome integrity. DNA Repair 9, 331–344 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hewish, M., Lord, C. J., Martin, S. A., Cunningham, D. & Ashworth, A. Mismatch repair deficient colorectal cancer in the era of personalized treatment. Nature Rev. Clin. Oncol. 7, 197–208 (2010).

    Article  Google Scholar 

  116. Lahue, R. S., Au, K. G. & Modrich, P. DNA mismatch correction in a defined system. Science 245, 160–164 (1989).

    Article  CAS  PubMed  Google Scholar 

  117. Song, L., Yuan, F. & Zhang, Y. Does a helicase activity help mismatch repair in eukaryotes? IUBMB Life 62, 548–553 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Sharma, S. et al. The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein. J. Biol. Chem. 278, 23487–23496 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Doherty, K. M. et al. RECQ1 helicase interacts with human mismatch repair factors that regulate genetic recombination. J. Biol. Chem. 280, 28085–28094 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Helleday, T. Amplifying tumour-specific replication lesions by DNA repair inhibitors — a new era in targeted cancer therapy. Eur. J. Cancer 44, 921–927 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Hegnauer, A. M. et al. An. N-terminal acidic region of Sgs1 interacts with Rpa70 and recruits Rad53 kinase to stalled forks. EMBO J. 31, 3768–3783 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bjergbaek, L., Cobb, J. A., Tsai-Pflugfelder, M. & Gasser, S. M. Mechanistically distinct roles for Sgs1p in checkpoint activation and replication fork maintenance. EMBO J. 24, 405–417 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Frei, C. & Gasser, S. M. The yeast Sgs1p helicase acts upstream of Rad53p in the DNA replication checkpoint and colocalizes with Rad53p in S-phase-specific foci. Genes Dev. 14, 81–96 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Doherty, K. M. et al. Physical and functional mapping of the RPA interaction domain of the Werner and Bloom syndrome helicases. J. Biol. Chem. 280, 29494–29505 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Sidorova, J. M., Li, N., Folch, A. & Monnat, R. J. Jr. The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest. Cell Cycle 7, 796–807 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Machwe, A., Xiao, L., Groden, J. & Orren, D. K. The Werner and Bloom syndrome proteins catalyze regression of a model replication fork. Biochemistry 45, 13939–13946 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Machwe, A., Karale, R., Xu, X., Liu, Y. & Orren, D. K. The Werner and Bloom syndrome proteins help resolve replication blockage by converting (regressed) Holliday junctions to functional replication forks. Biochemistry 50, 6774–6788 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Ralf, C., Hickson, I. D. & Wu, L. The Bloom's syndrome helicase can promote the regression of a model replication fork. J. Biol. Chem. 281, 22839–22846 (2006).

    Article  PubMed  Google Scholar 

  129. Berti, M. et al. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nature Struct. Mol. Biol. 20, 347–354 (2013).

    Article  CAS  Google Scholar 

  130. Fugger, K. et al. FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. Nature Commun. 4, 1423 (2013).

    Article  CAS  Google Scholar 

  131. Jeong, Y. T. et al. FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress. J. Cell Biol. 200, 141–149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kumaraswamy, E. & Shiekhattar, R. Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase. Mol. Cell. Biol. 27, 6733–6741 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gong, Z., Kim, J. E., Leung, C. C., Glover, J. N. & Chen, J. BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Mol. Cell 37, 438–446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Gari, K., Decaillet, C., Delannoy, M., Wu, L. & Constantinou, A. Remodeling of DNA replication structures by the branch point translocase FANCM. Proc. Natl Acad. Sci. USA 105, 16107–16112 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Yan, Z. et al. A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Mol. Cell 37, 865–878 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Betous, R. et al. SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Genes Dev. 26, 151–162 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yusufzai, T. & Kadonaga, J. T. HARP is an ATP-driven annealing helicase. Science 322, 748–750 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Euskirchen, G., Auerbach, R. K. & Snyder, M. SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J. Biol. Chem. 287, 30897–30905 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lai, A. Y. & Wade, P. A. Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nature Rev. Cancer 11, 588–596 (2011).

    Article  CAS  Google Scholar 

  140. McGlynn, P., Savery, N. J. & Dillingham, M. S. The conflict between DNA replication and transcription. Mol. Microbiol. 85, 12–20 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. de Septenville, A. L., Duigou, S., Boubakri, H. & Michel, B. Replication fork reversal after replication-transcription collision. PLoS Genet. 8, e1002622 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lutzmann, M. et al. MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol. Cell 47, 523–534 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Nishimura, K. et al. Mcm8 and Mcm9 form a complex that functions in homologous recombination repair induced by DNA interstrand crosslinks. Mol. Cell 47, 511–522 (2012). References 142 and 143 demonstrate that two MCM proteins that are traditionally known to be involved in DNA replication have a role in HR-mediated DNA repair that is important for cancer suppression and fertility.

    Article  CAS  PubMed  Google Scholar 

  144. Hartford, S. A. et al. Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germ-line stem cells and tumor suppression. Proc. Natl Acad. Sci. USA 108, 17702–17707 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Aguilera, A. & Garcia-Muse, T. R loops: from transcription byproducts to threats to genome stability. Mol. Cell 46, 115–124 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Sabouri, N., McDonald, K. R., Webb, C. J., Cristea, I. M. & Zakian, V. A. DNA replication through hard-to-replicate sites, including both highly transcribed RNA Pol II and Pol III genes, requires the S. pombe Pfh1 helicase. Genes Dev. 26, 581–593 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Steinacher, R., Osman, F., Dalgaard, J. Z., Lorenz, A. & Whitby, M. C. The DNA helicase Pfh1 promotes fork merging at replication termination sites to ensure genome stability. Genes Dev. 26, 594–602 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Bochman, M. L., Paeschke, K. & Zakian, V. A. DNA secondary structures: stability and function of G-quadruplex structures. Nature Rev. Genet. 13, 770–780 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Wu, Y. & Brosh, R. M. Jr. G-quadruplex nucleic acids and human disease. FEBS J. 277, 3470–3488 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Paeschke, K., Capra, J. A. & Zakian, V. A. DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase. Cell 145, 678–691 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ribeyre, C. et al. The yeast Pif1 helicase prevents genomic instability caused by G-quadruplex-forming CEB1 sequences in vivo. PLoS Genet. 5, e1000475 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Piazza, A. et al. Genetic instability triggered by G-quadruplex interacting Phen-DC compounds in Saccharomyces cerevisiae. Nucleic Acids Res. 38, 4337–4348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lopes, J. et al. G-quadruplex-induced instability during leading-strand replication. EMBO J. 30, 4033–4046 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Cheung, I., Schertzer, M., Rose, A. & Lansdorp, P. M. Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nature Genet. 31, 405–409 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Wu, Y., Shin-Ya, K. & Brosh, R. M. Jr. FANCJ helicase defective in Fanconia anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability. Mol. Cell. Biol. 28, 4116–4128 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Shin-Ya, K. et al. Telomestatin, a novel telomerase inhibitor from Streptomyces anulatus. J. Am. Chem. Soc. 123, 1262–1263 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. London, T. B. et al. FANCJ is a structure-specific DNA helicase associated with the maintenance of genomic G/C tracts. J. Biol. Chem. 283, 36132–36139 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Balasubramanian, S., Hurley, L. H. & Neidle, S. Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nature Rev. Drug Discov. 10, 261–275 (2011).

    Article  CAS  Google Scholar 

  159. Johnson, J. E., Cao, K., Ryvkin, P., Wang, L. S. & Johnson, F. B. Altered gene expression in the Werner and Bloom syndromes is associated with sequences having G-quadruplex forming potential. Nucleic Acids Res. 38, 1114–1122 (2010).

    Article  CAS  PubMed  Google Scholar 

  160. Corpet, A. & Almouzni, G. Making copies of chromatin: the challenge of nucleosomal organization and epigenetic information. Trends Cell Biol. 19, 29–41 (2009).

    Article  CAS  PubMed  Google Scholar 

  161. Sarkies, P., Reams, C., Simpson, L. J. & Sale, J. E. Epigenetic instability due to defective replication of structured DNA. Mol. Cell 40, 703–713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Sarkies, P. et al. FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA. Nucleic Acids Res. 40, 1485–1498 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Schwab, R. A., Nieminuszczy, J., Shin-Ya, K. & Niedzwiedz, W. FANCJ couples replication past natural fork barriers with maintenance of chromatin structure. J. Cell Biol. 201, 33–48 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kamath-Loeb, A. S., Lan, L., Nakajima, S., Yasui, A. & Loeb, L. A. Werner syndrome protein interacts functionally with translesion DNA polymerases. Proc. Natl Acad. Sci. USA 104, 10394–10399 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kamath-Loeb, A. S., Shen, J. C., Schmitt, M. W. & Loeb, L. A. The Werner syndrome exonuclease facilitates DNA degradation and high fidelity DNA polymerization by human DNA polymerase δ. J. Biol. Chem. 287, 12480–12490 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Dejardin, J. & Kingston, R. E. Purification of proteins associated with specific genomic loci. Cell 136, 175–186 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Sfeir, A. et al. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138, 90–103 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Opresko, P. L. et al. The Werner Syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol. Cell 14, 763–774 (2004).

    Article  CAS  PubMed  Google Scholar 

  169. Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nature Genet. 36, 877–882 (2004).

    Article  CAS  PubMed  Google Scholar 

  170. Du, X. et al. Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes. Mol. Cell. Biol. 24, 8437–8446 (2004). References 169 and 170 provide evidence using mouse models that WRN has an important role in suppressing chromosomal instability, cellular senescence and premature aging through its role in preserving the integrity of critically short telomeres.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Laud, P. R. et al. Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes Dev. 19, 2560–2570 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Crabbe, L., Verdun, R. E., Haggblom, C. I. & Karlseder, J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306, 1951–1953 (2004). This paper shows that in human cells the WRN helicase is required for the efficient replication of lagging-strand telomeric DNA. The study supports a model in which WRN resolves abnormal DNA structures that perturb replication fork progression.

    Article  CAS  PubMed  Google Scholar 

  173. Saharia, A. et al. Flap endonuclease 1 contributes to telomere stability. Curr. Biol. 18, 496–500 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Sharma, S. et al. WRN helicase and FEN-1 form a complex upon replication arrest and together process branch-migrating DNA structures associated with the replication fork. Mol. Biol. Cell 15, 734–750 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Fan, Q., Zhang, F., Barrett, B., Ren, K. & Andreassen, P. R. A role for monoubiquitinated FANCD2 at telomeres in ALT cells. Nucleic Acids Res. 37, 1740–1754 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Rhee, D. B. et al. FANCC suppresses short telomere-initiated telomere sister chromatid exchange. Hum. Mol. Genet. 19, 879–887 (2010).

    Article  CAS  PubMed  Google Scholar 

  177. Agrelo, R. et al. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc. Natl Acad. Sci. USA 103, 8822–8827 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zoppoli, G. et al. Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proc. Natl Acad. Sci. USA 109, 15030–15035 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Curtin, N. J. DNA repair dysregulation from cancer driver to therapeutic target. Nature Rev. Cancer 12, 801–817 (2012).

    Article  CAS  Google Scholar 

  180. Bouwman, P. & Jonkers, J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nature Rev. Cancer 12, 587–598 (2012).

    Article  CAS  Google Scholar 

  181. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005). References 181 and 182 demonstrate that inhibitors of the single-strand break DNA repair protein PARP1 are synthetic lethal in HR-deficient cells with mutations in breast cancer susceptibility proteins BRCA1 or BRCA2. This discovery paved the way for researchers to study synthetic lethality to improve cancer therapy.

    Article  CAS  PubMed  Google Scholar 

  183. Aggarwal, M. & Brosh, R. M. Jr. Hitting the bull's eye: novel directed cancer therapy through helicase-targeted synthetic lethality. J. Cell Biochem. 106, 758–763 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Moser, R. et al. MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency. Mol. Cancer Res. 10, 535–545 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Aggarwal, M., Sommers, J. A., Shoemaker, R. H. & Brosh, R. M. Jr. Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress. Proc. Natl Acad. Sci. USA 108, 1525–1530 (2011). This paper provides the first evidence that a human DNA helicase (WRN) could be inhibited by a small moleculein a cell-based system to modulate its role in helicase-dependent pathways that are important for DNA repair and the replication stress response.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Murai, J. et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 72, 5588–5599 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Nguyen, G. H. et al. A small molecule Inhibitor of the BLM helicase modulates chromosome stability in human cells. Chem. Biol. 20, 55–62 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Shay, J. W. & Bacchetti, S. A survey of telomerase activity in human cancer. Eur. J. Cancer 33, 787–791 (1997).

    Article  CAS  PubMed  Google Scholar 

  189. Buseman, C. M., Wright, W. E. & Shay, J. W. Is telomerase a viable target in cancer? Mutat. Res. 730, 90–97 (2012).

    Article  CAS  PubMed  Google Scholar 

  190. Li, Q., Xiang, J. F., Zhang, H. & Tang, Y. L. Searching drug-like anti-cancer compound(s) based on G-quadruplex ligands. Curr. Pharm. Des. 18, 1973–1983 (2012).

    Article  CAS  PubMed  Google Scholar 

  191. Gomez, D. et al. Telomestatin-induced telomere uncapping is modulated by POT1 through G-overhang extension in HT1080 human tumor cells. J. Biol. Chem. 281, 38721–38729 (2006).

    Article  CAS  PubMed  Google Scholar 

  192. Rodriguez, R. et al. A novel small molecule that alters shelterin integrity and triggers a DNA-damage response at telomeres. J. Am. Chem. Soc. 130, 15758–15759 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Rodriguez, R. et al. Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nature Chem. Biol. 8, 301–310 (2012). This study shows that a G4 ligand (pyridostatin) promotes growth arrest in human cancer cells by inducing replication- and transcription-dependent DNA damage in genomic regions prone to forming G-quadruplexes that are recognized by the human G4-resolving helicase PIF1.

    Article  CAS  Google Scholar 

  194. Muller, S. et al. Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells. Org. Biomol. Chem. 10, 6537–6546 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Gocha, A. R., Harris, J. & Groden, J. Alternative mechanisms of telomere lengthening: permissive mutations, DNA repair proteins and tumorigenic progression. Mutat. Res. 743–744, 142–150 (2013).

    Article  CAS  PubMed  Google Scholar 

  196. Mackintosh, S. G. & Raney, K. D. DNA unwinding and protein displacement by superfamily 1 and superfamily 2 helicases. Nucleic Acids Res. 34, 4154–4159 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Rad, B. & Kowalczykowski, S. C. Efficient coupling of ATP hydrolysis to translocation by RecQ helicase. Proc. Natl Acad. Sci. USA 109, 1443–1448 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Sarlos, K., Gyimesi, M. & Kovacs, M. RecQ helicase translocates along single-stranded DNA with a moderate processivity and tight mechanochemical coupling. Proc. Natl Acad. Sci. USA 109, 9804–9809 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Patel, S. S. & Picha, K. M. Structure and function of hexameric helicases. Annu. Rev. Biochem. 69, 651–697 (2000).

    Article  CAS  PubMed  Google Scholar 

  200. Spies, M., Amitani, I., Baskin, R. J. & Kowalczykowski, S. C. RecBCD enzyme switches lead motor subunits in response to chi recognition. Cell 131, 694–705 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Wong, I. & Lohman, T. M. Allosteric effects of nucleotide cofactors on Escherichia coli Rep helicase-DNA binding. Science 256, 350–355 (1992).

    Article  CAS  PubMed  Google Scholar 

  202. Wu, Y. et al. Fanconi anemia Group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein-DNA complexes. Blood 116, 3780–3791 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Zittel, M. C. & Keck, J. L. Coupling DNA-binding and ATP hydrolysis in Escherichia coli RecQ: role of a highly conserved aromatic-rich sequence. Nucleic Acids Res. 33, 6982–6991 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Wu, Y. et al. The Q Motif of FANCJ DNA helicase regulates its dimerization, DNA binding, and DNA repair function. J. Biol. Chem. 287, 21699–21716 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Heyer, W. D., Ehmsen, K. T. & Liu, J. Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet. 44, 113–139 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Myong, S., Rasnik, I., Joo, C., Lohman, T. M. & Ha, T. Repetitive shuttling of a motor protein on DNA. Nature 437, 1321–1325 (2005).

    Article  CAS  PubMed  Google Scholar 

  207. Myong, S., Bruno, M. M., Pyle, A. M. & Ha, T. Spring-loaded mechanism of DNA unwinding by hepatitis C virus NS3 helicase. Science 317, 513–516 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Yodh, J. G., Stevens, B. C., Kanagaraj, R., Janscak, P. & Ha, T. BLM helicase measures DNA unwound before switching strands and hRPA promotes unwinding reinitiation. EMBO J. 28, 405–416 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Sun, B. et al. ATP-induced helicase slippage reveals highly coordinated subunits. Nature 478, 132–135 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Pike, A. C. et al. Structure of the human RECQ1 helicase reveals a putative strand-separation pin. Proc. Natl Acad. Sci. USA 106, 1039–1044 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Kuper, J., Wolski, S. C., Michels, G. & Kisker, C. Functional and structural studies of the nucleotide excision repair helicase XPD suggest a polarity for DNA translocation. EMBO J. 31, 494–502 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Brosh, R. M. Jr & Bohr, V. A. Human premature aging, DNA repair and RecQ helicases. Nucleic Acids Res. 35, 7527–7544 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Sharma, S. et al. Biochemical analysis of the DNA unwinding and strand annealing activities catalyzed by human RECQ1. J. Biol. Chem. 280, 28072–28084 (2005).

    Article  CAS  PubMed  Google Scholar 

  214. Mazina, O. M., Rossi, M. J., Deakyne, J. S., Huang, F. & Mazin, A. V. Polarity and bypass of DNA heterology during branch migration of Holliday junctions by human RAD54, BLM, and RECQ1 proteins. J. Biol. Chem. 287, 11820–11832 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Wu, L. & Hickson, I. D. The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426, 870–874 (2003). This paper provides the first molecular evidence for how the BLM helicase prevents SCE during the repair of replication-associated DNA damage, and has implications for understanding mechanisms that suppress tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  216. Long, D. T., Raschle, M., Joukov, V. & Walter, J. C. Mechanism of RAD51-dependent DNA interstrand cross-link repair. Science 333, 84–87 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Brosh, R. M. Jr et al. Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity. EMBO J. 20, 5791–5801 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Sharma, S. et al. Stimulation of flap endonuclease-1 by the Bloom's syndrome protein. J. Biol. Chem. 279, 9847–9856 (2004).

    Article  CAS  PubMed  Google Scholar 

  219. Wang, W. & Bambara, R. A. Human Bloom protein stimulates flap endonuclease 1 activity by resolving DNA secondary structure. J. Biol. Chem. 280, 5391–5399 (2005).

    Article  CAS  PubMed  Google Scholar 

  220. Chan, N. L. et al. The Werner syndrome protein promotes CAG/CTG repeat stability by resolving large (CAG)(n)/(CTG)(n) hairpins. J. Biol. Chem. 287, 30151–30156 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Henry, R. A., Balakrishnan, L., Ying-Lin, S. T., Campbell, J. L. & Bambara, R. A. Components of the secondary pathway stimulate the primary pathway of eukaryotic Okazaki fragment processing. J. Biol. Chem. 285, 28496–28505 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. McGlynn, P. Helicases that underpin replication of protein-bound DNA in Escherichia coli. Biochem. Soc. Trans. 39, 606–610 (2011).

    Article  CAS  PubMed  Google Scholar 

  223. Yin, J. et al. BLAP75, an essential component of Bloom's syndrome protein complexes that maintain genome integrity. EMBO J. 24, 1465–1476 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Mao, F. J., Sidorova, J. M., Lauper, J. M., Emond, M. J. & Monnat, R. J. The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage. Cancer Res. 70, 6548–6555 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Popuri, V. et al. Recruitment and retention dynamics of RECQL5 at DNA double strand break sites. DNA Repair 11, 624–635 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Peng, M., Litman, R., Jin, Z., Fong, G. & Cantor, S. B. BACH1 is a DNA repair protein supporting BRCA1 damage response. Oncogene 25, 2245–2253 (2006).

    Article  CAS  PubMed  Google Scholar 

  227. Farina, A. et al. Studies with the human cohesin establishment factor, ChlR1. Association of ChlR1 with Ctf18-RFC and Fen1. J. Biol. Chem. 283, 20925–20936 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Parish, J. L. et al. The DNA helicase ChlR1 is required for sister chromatid cohesion in mammalian cells. J. Cell Sci. 119, 4857–4865 (2006).

    Article  CAS  PubMed  Google Scholar 

  229. Bhattacharya, C., Wang, X. & Becker, D. The DEAD/DEAH box helicase, DDX11, is essential for the survival of advanced melanomas. Mol. Cancer 11, 82 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Institute on Aging (NIA). I thank J. Burril of the NIA Visual Media Section for artwork in drafts of figures 2,3 and 5. I express gratitude to M. Seidman, Y. Liu, V. Bohr and W. Wang (NIA-NIH) for critically reading the manuscript, and S. Matson (University of North Carolina at Chapel Hill) for introducing me to the helicase field and for providing strong mentorship. I apologize to those researchers whose published work on DNA helicases was not cited owing to length restrictions.

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  1. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health (NIH), NIH Biomedical Research Center, 251 Bayview Boulevard, Baltimore, 21224, Maryland, USA

    Robert M. Brosh Jr.

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Glossary

Poikiloderma

A skin condition that consists of areas of increased and decreased pigmentation, prominent blood vessels and thinning of the skin.

Homologous recombination

(HR). A type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. HR is most widely used by cells to accurately repair damage that involves both strands, such as double-strand breaks or interstrand DNA crosslinks.

Base-excision repair

(BER). A DNA repair pathway that operates on small DNA lesions such as oxidized or reduced bases, fragmented or non-bulky adducts, or those produced by methylating agents. The resulting single-strand break can be processed by either short-patch BER (through which a single nucleotide is replaced) or long-patch BER (through which 2–10 new nucleotides are synthesized).

Transcription Factor IIH

(TFIIH). A general transcription factor complex composed of multiple protein subunits that enables formation of the RNA polymerase II pre-initiation complex. TFIIH is also implicated in nucleotide-excision repair (NER).

Nucleotide-excision repair

(NER). This pathway recognizes bulky distortions in the DNA that occur after ultraviolet radiation or chemotherapy. Recognition of these distortions leads to the removal of a short single-stranded DNA segment that includes the lesion, creating a single-strand gap in the DNA, which is subsequently filled by a DNA polymerase.

G-quadruplex

(G4). A four-stranded nucleic acid structure stabilized by non-Watson–Crick Hoogsteen base-pairing within stacks of four planar-orientated guanosine nucleotides. G-quadruplex structures can form within or between G-rich strands of telomeric DNA or other G-rich sequences.

Intra-S-phase checkpoint

Single-stranded DNA created at the stalled replication fork generates a signal mediated by phosphorylation of target proteins (for example, mammalian ATR) that prevents the cell cycle from progressing to the G2 phase until replication is complete.

DNA charge transport

The process of transporting electrons along the axis of a double helical DNA molecule through the overlapping π-orbitals of stacked DNA base pairs.

Slippage

When a helicase loses its firm grasp on single-stranded DNA, causing it to slide backwards owing to re-annealing of complementary strands at the DNA fork.

Translesion synthesis

A DNA damage tolerance process that allows replication past DNA lesions. If the normal replicative polymerase cannot insert a base owing to damage in the template strand, it is often replaced by a lower-fidelity translesion polymerase.

Non-homologous end-joining

(NHEJ). Unlike homologous recombination-mediated repair, NHEJ rejoins broken ends of DNA following double-strand breaks without using a homologous DNA template and can therefore be accompanied by loss of nucleotides and errors.

Mismatch repair

(MMR). A process that acts during DNA replication to correct base pairing errors made by the DNA polymerases.

RAD51–double-stranded DNA filaments

During an early stage of homologous recombination, the major eukaryotic recombinase RAD51 forms nucleoprotein filaments on double-stranded DNA to initiate the homology search and exchange of DNA strands. Filaments can also occur on single-stranded DNA.

Synthetic lethality

Cell death resulting from the combined inactivation or inhibition of two genes or gene products that are non-lethal when inactivated individually. Synthetic lethality can occur between genes and small molecules, which may lead to anticancer therapies.

Sister-chromatid exchange

(SCE). A crossing-over event between sister chromatids, leading to the exchange of homologous stretches of DNA sequence.

G4 ligand

A typically planar aromatic small molecule that preferentially binds G-quadruplex (G4) DNA with high affinity. There are also proteins that preferentially bind G4 DNA.

Shelterin complex

A six-protein complex that localizes to the terminal TTAGGG repeats of mammalian chromosome ends, enabling cells to distinguish their natural chromosome ends from DNA breaks. The shelterin complex represses DNA repair reactions and regulates telomerase-based telomere maintenance.

T-loops

The 3′ single-stranded telomere DNA overhang circles around and hybridizes to the complementary strand of the adjacent double-stranded DNA to create a displacement loop (D-loop) by displacing one of the strands. T-loops are stabilized by telomere-binding proteins.

Alternative lengthening of telomeres

(ALT). A recombination-based mechanism that allows telomere length maintenance in the absence of telomerase activity.

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Brosh, R. DNA helicases involved in DNA repair and their roles in cancer. Nat Rev Cancer 13, 542–558 (2013). https://doi.org/10.1038/nrc3560

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