Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

RecQ helicases: caretakers of the genome

Nature Reviews Cancer volume 3, pages 169–178 (2003)Cite this article

Key Points

  • RecQ helicases represent a highly conserved family that is required for the maintenance of genome integrity.

  • In humans, defects in any of three RecQ family members (BLM, WRN or RECQ4) give rise to cancer predisposition disorders. These are Bloom's, Werner's and Rothmund–Thomson syndromes, respectively.

  • RecQ helicases are considered to be 'caretaker' tumour suppressors that suppress neoplastic transformation through control of chromosomal stability. Many other similar caretakers are functionally linked to the RecQ helicases, indicating a possible common molecular basis for tumorigenesis in several apparently distinct cancer predisposition disorders.

  • Human RecQ helicases make multiple physical interactions with other nuclear proteins that are required for DNA metabolism. Many of these interactions have a functional effect on the activity of one or both partners.

  • RecQ helicases are proposed to function at the interface between DNA replication and recombination to 'repair' damaged replication forks.

Abstract

RecQ helicases are highly conserved from bacteria to man. Germline mutations in three of the five known family members in humans give rise to debilitating disorders that are characterized by, amongst other things, a predisposition to the development of cancer. One of these disorders — Bloom's syndrome — is uniquely associated with a predisposition to cancers of all types. So how do RecQ helicases protect against cancer? They seem to maintain genomic stability by functioning at the interface between DNA replication and DNA repair.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The RecQ helicase family.
Figure 2: Selected mutations found in BLM and WRN in affected individuals.
Figure 3: Selected protein partners for BLM and WRN.
Figure 4: Interactions between different caretaker tumour-suppressor proteins.
Figure 5: Potential roles of RecQ helicases in defending genome integrity during DNA replication.

Similar content being viewed by others

References

  1. Soultanas, P. & Wigley, D. B. Unwinding the 'Gordian knot' of helicase action. Trends Biochem. Sci. 26, 47–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Chakraverty, R. K. & Hickson, I. D. Defending genome integrity during DNA replication: a proposed role for RecQ family helicases. BioEssays 21, 286–294 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Karow, J. K., Wu, L. & Hickson, I. D. RecQ family helicases: roles in cancer and aging. Curr. Opin. Genet. Dev. 10, 32–38 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. van Brabant, A. J., Stan, R. & Ellis, N. A. DNA helicases, genomic instability, and human genetic disease. Annu. Rev. Genomics Hum. Genet. 1, 409–459 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Mohaghegh, P. & Hickson, I. D. DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum. Mol. Genet. 10, 741–746 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Nakayama, H. et al. Isolation and genetic characterization of a thymineless death-resistant mutant of Escherichia coli K12: identification of a new mutation (recQ1) that blocks the RecF recombination pathway. Mol. Gen. Genet. 195, 474–480 (1984).

    Article  CAS  PubMed  Google Scholar 

  7. Morozov, V., Mushegian, A. R., Koonin, E. V. & Bork, P. A putative nucleic acid-binding domain in Bloom's and Werner's syndrome helicases. Trends Biochem. Sci. 22, 417–418 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Liu, Z. et al. The three-dimensional structure of the HRDC domain and implications for the Werner and Bloom syndrome proteins. Structure Fold. Des. 7, 1557–1566 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Kaneko, H. et al. BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal. Biochem. Biophys. Res. Commun. 240, 348–353 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Matsumoto, T., Shimamoto, A., Goto, M. & Furuichi, Y. Impaired nuclear localization of defective DNA helicases in Werner's syndrome. Nature Genet. 16, 335–336 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Huang, S. et al. The premature ageing syndrome protein, WRN, is a 3′–5′ exonuclease. Nature Genet. 20, 114–116 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Kamath-Loeb, A. S., Shen, J. C., Loeb, L. A. & Fry, M. Werner syndrome protein. II. Characterization of the integral 3′–5′ DNA exonuclease. J. Biol. Chem. 273, 34145–34150 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Shen, J. C. et al. Werner syndrome protein. I. DNA helicase and DNA exonuclease reside on the same polypeptide. J. Biol. Chem. 273, 34139–34144 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Opresko, P. L., Laine, J. P., Brosh, R. M. Jr, Seidman, M. M. & Bohr, V. A. Coordinate action of the helicase and 3′ to 5′ exonuclease of Werner syndrome protein. J. Biol. Chem. 276, 44677–44687 (2001). References 11–14 show that the WRN protein is a combined helicase/nuclease, unlike other RecQ-family helicases.

    Article  CAS  PubMed  Google Scholar 

  15. Shimamoto, A., Nishikawa, K., Kitao, S. & Furuichi, Y. Human RecQ5β, a large isomer of RecQ5 DNA helicase, localizes in the nucleoplasm and interacts with topoisomerases 3α and 3β. Nucleic Acids Res. 28, 1647–1655 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ellis, N. A. et al. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83, 655–666 (1995). Reports the identification of the gene that is defective in Bloom's syndrome as encoding a RecQ helicase.

    Article  CAS  PubMed  Google Scholar 

  17. Yu, C. et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 (1996). Reports the identification of the gene that is defective in Werner's syndrome as encoding a RecQ helicase.

    Article  CAS  PubMed  Google Scholar 

  18. Kitao, S. et al. Mutations in RECQL4 cause a subset of cases of Rothmund–Thomson syndrome. Nature Genet. 22, 82–84 (1999). Reports the identification of the gene that is defective in Rothmund–Thomson syndrome as encoding a RecQ helicase.

    Article  CAS  PubMed  Google Scholar 

  19. German, J. Bloom's syndrome. Dermatol. Clin. 13, 7–18 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Oshima, J. The Werner syndrome protein: an update. Bioessays 22, 894–901 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Shen, J. -L. & Loeb, L. A. The Werner syndrome gene. Trends Genet. 16, 213–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Vennos, E. M. & James, W. D. Rothmund–Thomson syndrome. Dermatol. Clin. 13, 143–150 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Wang, L. L. et al. Clinical manifestations in a cohort of 41 Rothmund–Thomson syndrome patients. Am. J. Med. Genet. 102, 11–17 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Moser, M. J., Oshima, J. & Monnat, R. J., Jr . WRN mutations in Werner syndrome. Hum. Mutat. 13, 271–279 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Straughen, J. E. et al. A rapid method for detecting the predominant Ashkenazi Jewish mutation in the Bloom's syndrome gene. Hum. Mutat. 11, 175–178 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Levitt, N. C. & Hickson, I. D. Caretaker tumour suppressor genes that defend genome integrity. Trends Mol. Med. 8, 179–186 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Calin, G. et al. Somatic frameshift mutations in the Bloom syndrome BLM gene are frequent in sporadic gastric carcinomas with microsatellite mutator phenotype. BMC Genet. 2, 14 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Knudson, A. G. Jr . Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gruber, S. B. et al. BLM heterozygosity and the risk of colorectal cancer. Science 297, 2013 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Goss, K. H. et al. Enhanced tumor formation in mice heterozygous for Blm mutation. Science 297, 2051–2053 (2002). This paper, as well as reference 30, indicates that BLM heterozygosity predisposes humans and mice to cancer.

    Article  PubMed  CAS  Google Scholar 

  32. Oakley, T. J. & Hickson, I. D. Defending genome integrity during S-phase: putative roles for RecQ helicases and topoisomerase III. DNA Repair 1, 1–33 (2002).

    Article  Google Scholar 

  33. Lonn, U., Lonn, S., Nylen, U., Winblad, G. & German, J. An abnormal profile of DNA replication intermediates in Bloom's syndrome. Cancer Res. 50, 3141–3145 (1990).

    CAS  PubMed  Google Scholar 

  34. Chaganti, R. S., Schonberg, S. & German, J. A manyfold increase in sister chromatid exchanges in Bloom's syndrome lymphocytes. Proc. Natl Acad. Sci. USA 71, 4508–4512 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sonoda, E. et al. Sister chromatid exchanges are mediated by homologous recombination in vertebrate cells. Mol. Cell. Biol. 19, 5166–5169 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Prince, P. R., Emond, M. J. & Monnat, R. J., Jr . Loss of Werner syndrome protein function promotes aberrant mitotic recombination. Genes Dev. 15, 933–938 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Saintigny, Y., Makienko, K., Swanson, C., Emond, M. J. & Monnat, R. J. Jr . Homologous recombination resolution defect in Werner syndrome. Mol. Cell. Biol. 22, 6971–6978 (2002). Indicates that the WRN protein is involved in the resolution of recombinase structures.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fukuchi, K., Martin, G. M. & Monnat, R. J. Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Natl Acad. Sci. USA 86, 5893–5897 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chester, N., Kuo, F., Kozak, C., O'Hara, C. D. & Leder, P. Stage-specific apoptosis, developmental delay, and embryonic lethality in mice homozygous for a targeted disruption in the murine Bloom's syndrome gene. Genes Dev. 12, 3382–3393 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Luo, G. et al. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nature Genet. 26, 424–429 (2000). Identified a viable, cancer-prone mouse for Bloom's syndrome.

    Article  CAS  PubMed  Google Scholar 

  41. Lebel, M. & Leder, P. A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc. Natl Acad. Sci. USA 95, 13097–13102 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lebel, M., Cardiff, R. D. & Leder, P. Tumorigenic effect of nonfunctional p53 or p21 in mice mutant in the Werner syndrome helicase. Cancer Res. 61, 1816–1819 (2001).

    CAS  PubMed  Google Scholar 

  43. Mohaghegh, P., Karow, J. K., Brosh, R. M. Jr, Bohr, V. A. Jr & Hickson, I. D. The Bloom's and Werner's syndrome proteins are DNA structure-specific helicases. Nucleic Acids Res. 29, 2843–2849 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun, H., Karow, J. K., Hickson, I. D. & Maizels, N. The Bloom's syndrome helicase unwinds G4 DNA. J. Biol. Chem. 273, 27587–27592 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Fry, M. & Loeb, L. A. Human werner syndrome DNA helicase unwinds tetrahelical structures of the fragile X syndrome repeat sequence d(CGG)n. J. Biol. Chem. 274, 12797–12802 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Sun, H., Bennett, R. J. & Maizels, N. The Saccharomyces cerevisiae Sgs1 helicase efficiently unwinds G-G paired DNAs. Nucleic Acids Res. 27, 1978–1984 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu, X. & Maizels, N. Substrate-specific inhibition of RecQ helicase. Nucleic Acids Res. 29, 1765–1771 (2001). References 43–47 revealed that G-quadruplex DNA is a preferred substrate for RecQ helicases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Han, H. & Hurley, L. H. G-quadruplex DNA: a potential target for anti-cancer drug design. Trends Pharmacol. Sci. 21, 136–142 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Karow, J. K., Constantinou, A., Li, J. L., West, S. C. & Hickson, I. D. The Bloom's syndrome gene product promotes branch migration of Holliday junctions. Proc. Natl Acad. Sci. USA 97, 6504–6508 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Constantinou, A. et al. Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest. EMBO Rep. 1, 80–84 (2000). References 49 and 50 identified BLM and WRN as Holliday junction branch-migration proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. West, S. C. Processing of recombination intermediates by the RuvABC proteins. Annu. Rev. Genet. 31, 213–244 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Yankiwski, V., Marciniak, R. A., Guarente, L. & Neff, N. F. Nuclear structure in normal and Bloom syndrome cells. Proc. Natl Acad. Sci. USA 97, 5214–5219 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sanz, M. M., Proytcheva, M., Ellis, N. A., Holloman, W. K. & German, J. BLM, the Bloom's syndrome protein, varies during the cell cycle in its amount, distribution, and co-localization with other nuclear proteins. Cytogenet. Cell Genet. 91, 217–223 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Zhong, S. et al. A role for PML and the nuclear body in genomic stability. Oncogene 18, 7941–7947 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Hodges, M., Tissot, C., Howe, K., Grimwade, D. & Freemont, P. S. Structure, organization, and dynamics of promyelocytic leukemia protein nuclear bodies. Am. J. Hum. Genet. 63, 297–304 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ruggero, D., Wang, Z. G. & Pandolfi, P. P. The puzzling multiple lives of PML and its role in the genesis of cancer. Bioessays 22, 827–835 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Wu, L., Davies, S. L., Levitt, N. C. & Hickson, I. D. Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51. J. Biol. Chem. 276, 19375–19381 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Bischof, O. et al. Regulation and localization of the Bloom syndrome protein in response to DNA damage. J. Cell Biol. 153, 367–380 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pedrazzi, G. et al. Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Nucleic Acids Res. 29, 4378–4386 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, Y. et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927–939 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Gray, M. D., Wang, L., Youssoufian, H., Martin, G. M. & Oshima, J. Werner helicase is localized to transcriptionally active nucleoli of cycling cells. Exp. Cell Res. 242, 487–494 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Marciniak, R. A., Lombard, D. B., Johnson, F. B. & Guarente, L. Nucleolar localization of the Werner syndrome protein in human cells. Proc. Natl Acad. Sci. USA 95, 6887–6892 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sakamoto, S. et al. Werner helicase relocates into nuclear foci in response to DNA damaging agents and co-localizes with RPA and Rad51. Genes Cells 6, 421–430 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Spillare, E. A. et al. p53-mediated apoptosis is attenuated in Werner syndrome cells. Genes Dev. 13, 1355–1360 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Blander, G. et al. Physical and functional interaction between p53 and the Werner's syndrome protein. J. Biol. Chem. 274, 29463–29469 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Wang, X. W. et al. Functional interaction of p53 and BLM DNA helicase in apoptosis. J. Biol. Chem. 276, 32948–32955 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Brosh, R. M. Jr . et al. p53 Modulates the exonuclease activity of Werner syndrome protein. J. Biol. Chem. 276, 35093–35102 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Yang, Q. et al. The processing of Holliday junctions by BLM and WRN helicases is regulated by p53. J. Biol. Chem. 277, 31980–31987 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Brosh, R. M. Jr . et al. Functional and physical interaction between WRN helicase and human replication protein A. J. Biol. Chem. 274, 18341–18350 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Shen, J. C., Gray, M. D., Oshima, J. & Loeb, L. A. Characterization of Werner syndrome protein DNA helicase activity: directionality, substrate dependence and stimulation by replication protein A. Nucleic Acids Res. 26, 2879–2885 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brosh, R. M. Jr et al. Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity. J. Biol. Chem. 275, 23500–23508 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. von Kobbe, C. et al. Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins. J. Biol. Chem. 277, 22035–22044 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Gangloff, S., McDonald, J. P., Bendixen, C., Arthur, L. & Rothstein, R. The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase. Mol. Cell. Biol. 14, 8391–8398 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bennett, R. J., Noirot-Gros, M. F. & Wang, J. C. Interaction between yeast sgs1 helicase and DNA topoisomerase III. J. Biol. Chem. 275, 26898–26905 (2000).

    CAS  PubMed  Google Scholar 

  75. Harmon, F. G., DiGate, R. J. & Kowalczykowski, S. C. RecQ helicase and topoisomerase III comprise a novel DNA strand passage function: a conserved mechanism for control of DNA recombination. Mol. Cell 3, 1–20 (1999).

    Article  Google Scholar 

  76. Wu, L. et al. The Bloom's syndrome gene product interacts with topoisomerase III. J. Biol. Chem. 275, 9636–9644 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Johnson, F. B. et al. Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells. Cancer Res. 60, 1162–1167 (2000).

    CAS  PubMed  Google Scholar 

  78. Wu, L. & Hickson, I. D. The Bloom's syndrome helicase stimulates the activity of human topoisomerase III alpha. Nucleic Acids Res. 30, 4823–4829 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Stewart, G. S. et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99, 577–587 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Rotman, G. & Shiloh, Y. ATM: a mediator of multiple responses to genotoxic stress. Oncogene 18, 6135–6144 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Featherstone, C. & Jackson, S. P. DNA repair: the Nijmegen breakage syndrome protein. Curr. Biol. 8, R622–R625 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Beamish, H. et al. Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM. J. Biol. Chem. 277, 30515–30523 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Langland, G. et al. The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair. J. Biol. Chem. 276, 30031–30035 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Buermeyer, A. B., Deschenes, S. M., Baker, S. M. & Liskay, R. M. Mammalian DNA mismatch repair. Annu. Rev. Genet. 33, 533–564 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Myung, K., Datta, A., Chen, C. & Kolodner, R. D. SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination. Nature Genet. 27, 113–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Lebel, M., Spillare, E. A., Harris, C. C. & Leder, P. The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J. Biol. Chem. 274, 37795–37799 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Brosh, R. M. Jr, Driscoll, H. C., Dianov, G. L. & Sommers, J. A. Biochemical characterization of the WRN–FEN-1 functional interaction. Biochemistry 41, 12204–12216 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. 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 

  89. Kamath-Loeb, A. S., Loeb, L. A., Johansson, E., Burgers, P. M. & Fry, M. Interactions between the Werner syndrome helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence. J. Biol. Chem. 276, 16439–16446 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Mol, C. D., Parikh, S. S., Putnam, C. D., Lo, T. P. & Tainer, J. A. DNA repair mechanisms for the recognition and removal of damaged DNA bases. Annu. Rev. Biophys. Biomol. Struct. 28, 101–128 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Li, B. & Comai, L. Functional interaction between Ku and the Werner syndrome protein in DNA end processing. J. Biol. Chem. 275, 28349–28352 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. 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 

  93. Orren, D. K. et al. A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA. Nucleic Acids Res. 29, 1926–1934 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Karmakar, P. et al. Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation. J. Biol. Chem. 277, 18291–18302 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Li, B. & Comai, L. Displacement of DNA-PKcs from DNA ends by the Werner syndrome protein. Nucleic Acids Res. 30, 3653–3661 (2002). References 91–95 show that WRN is complexed with the DNA-dependent protein kinase in human cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cox, M. M. Recombinational DNA repair of damaged replication forks in Escherichia coli: questions. Annu. Rev. Genet. 35, 53–82 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Cox, M. M. et al. The importance of repairing stalled replication forks. Nature 404, 37–41 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Kowalczykowski, S. C. Initiation of genetic recombination and recombination-dependent replication. Trends Biochem. Sci. 25, 156–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Postow, L. et al. Positive torsional strain causes the formation of a four-way junction at replication forks. J. Biol. Chem. 276, 2790–2796 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. McGlynn, P. & Lloyd, R. G. Rescue of stalled replication forks by RecG: simultaneous translocation on the leading and lagging strand templates supports an active DNA unwinding model of fork reversal and Holliday junction formation. Proc. Natl Acad. Sci. USA 98, 8227–8234 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wu, L. & Hickson, I. D. RecQ helicases and topoisomerases: components of a conserved complex for the regulation of genetic recombination. Cell Mol. Life Sci. 58, 894–901 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    Article  CAS  PubMed  Google Scholar 

  103. Olovnikov, A. M. Principles of marginotomy in template synthesis of polynucleotides. Doklady. Biochem. 210, 394–397 (1971).

    Google Scholar 

  104. Cong, Y. S., Wright, W. E. & Shay, J. W. Human telomerase and its regulation. Microbiol. Mol. Biol. Rev. 66, 407–425 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nugent, C. I. & Lundblad, V. The telomerase reverse transcriptase: components and regulation. Genes Dev. 12, 1073–1085 (1998).

    Article  CAS  PubMed  Google Scholar 

  106. McEachern, M. J., Krauskopf, A. & Blackburn, E. H. Telomeres and their control. Annu. Rev. Genet. 34, 331–358 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Huang, P. et al. SGS1 is required for telomere elongation in the absence of telomerase. Curr. Biol. 11, 125–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Cohen, H. & Sinclair, D. A. Recombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase. Proc. Natl Acad. Sci. USA 98, 3174–3179 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Johnson, F. B. et al. The Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase. EMBO J. 20, 905–913 (2001). References 107–109 identified a role for RecQ helicases in telomere maintenance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yeager, T. R. et al. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res. 59, 4175–4179 (1999).

    CAS  PubMed  Google Scholar 

  111. Opresko, P. L. et al. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J. Biol. Chem. 277, 41110–41119 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Gao, W., Khang, C. H., Park, S. Y., Lee, Y. H. & Kang, S. Evolution and organization of a highly dynamic, subtelomeric helicase gene family in the rice blast fungus Magnaporthe grisea. Genetics 162, 103–112 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ohsugi, I. et al. Telomere repeat DNA forms a large non-covalent complex with unique cohesive properties which is dissociated by Werner syndrome DNA helicase in the presence of replication protein A. Nucleic Acids Res. 28, 3642–3648 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I would like to thank L. Wu, V. Macaulay, C. Norbury and P. McHugh for comments on the manuscript, J. Pepper for preparation of the manuscript and Cancer Research UK for financial support.

Author information

Authors and Affiliations

  1. Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK

    Ian D. Hickson

Authors
  1. Ian D. Hickson
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

LocusLink

Apc

ATM

Blm

BLM

BRCA1

BRCA2

DNA topoisomerase III

FEN1

KU70

KU80

MLH1

MRE11

MSH2

NBS1

p53

PCNA

POLδ

RAD50

RAD51

RAD52

RECQ4

RECQ5

RECQL

RPA

TRF2

Trp53

WRN

OMIM

ataxia telangiectasia

Bloom's syndrome

Nijmegen breakage syndrome

Rothmund–Thomson syndrome

Werner's syndrome

Saccharomyces Genome Database

Rad51

Sgs1

INFORMATION

Mutation registry for Bloom syndrome

Glossary

PROGEROID SYNDROME

A genetic disorder that leads to the premature onset of several features of the ageing process.

POIKILODERMA

Reticulated cutaneous plaques.

ALOPECIA

Extensive hair loss.

NONSENSE MUTATION

A mutation that results in the introduction of a stop codon to cause the premature termination of the protein.

MUTATOR PHENOTYPE

Genetic or epigenetic abnormality that leads to an elevated rate of mutation. Often caused by defects in the DNA mismatch-repair pathway.

HYPOMORPHIC MUTATION

An allele that results in a reduction, but not the elimination, of wild-type levels of gene product or activity, often causing a less severe phenotype than a loss-of-function (or null) allele.

POLYMORPHISMS

Occurrence, at a single genetic locus, of two or more alleles that differ in nucleotide sequence.

APC

A gene that, when defective, predisposes individuals to colorectal adenomas and carcinomas.

HAPLOINSUFFICIENCY

A situation in which a loss-of-function phenotype is produced by mutating one allele of a gene in a diploid cell, even though the other allele is wild type.

QUADRIRADIAL CHROMOSOMES

Four-armed chromosomes that are probably formed by recombination between two chromosomes (usually two homologues). They might represent unresolved recombination reactions 'caught in the act'.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.

G-QUADRUPLEX DNA

G-quadruplexes are highly-stable, non-Watson–Crick DNA secondary structures that can arise at guanine-rich genomic loci, including the c-MYC gene promoter, immunoglobulin heavy chain switch regions and the G-rich telomeric repeat DNA that caps the ends of eukaryotic chromosomes.

DNA-MISMATCH REPAIR

A system to repair base-pair mismatches that can occur, for instance, during DNA replication. Mutations in genes that encode components of the mismatch-repair machinery result in microsatellite instability (MIN).

HEREDITARY NON-POLYPOSIS COLORECTAL CANCER

An inherited predisposition to colorectal cancer, generally caused by a germline mutation in a mismatch-repair gene.

LONG-PATCH BASE-EXCISION REPAIR (BER)

A system to repair DNA base damage, such as alkylation or oxidation. The 'long-path' subpathway of BER involves replicative polymerases and the resynthesis of a patch of new DNA at the repair site that is 2–10 base pairs in length. By contrast, short-patch BER involves a single nucleotide insertion.

NON-HOMOLOGOUS END-JOINING PATHWAY

A system to repair DNA double-strand breaks through the direct re-ligation of the broken ends.

REPLISOME

The multienzyme complex that catalyses replication of chromosomal DNA.

END-REPLICATION PROBLEM

The inherent inability of the DNA-replication machinery to replicate to the very end of a chromosome because of the requirement for lagging-strand replication to initiate from an RNA primer.

ATYPICAL PML BODIES

In ALT cells, PML bodies are smaller and more numerous, and seem to coincide with telomeric DNA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hickson, I. RecQ helicases: caretakers of the genome. Nat Rev Cancer 3, 169–178 (2003). https://doi.org/10.1038/nrc1012

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1012

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing