The Werner syndrome protein is a DNA helicase (original) (raw)

Nature Genetics volume 17, pages 100–103 (1997)Cite this article

Abstract

Werner syndrome (WS) is an uncommon autosomal recessive disorder characterized by premature aging. The clinical manifestations of WS, including atherosclerosis and osteoporosis, appear early in adulthood, and death in the fourth to sixth decade commonly ensues from myocardial infarction or cancer1,2. In accord with the aging phenotype, cells from WS patients have a reduced replicative life span in culture3. Genomic instability is observed at the cytogenetic level in the form of chromosome breaks and translations4 and at the molecular level by multiple large deletions5. The Werner syndrome gene (WRN) has recently been cloned6. The predicted product is a 1,432-amino-acid protein whose central domain is homologous to members of the RecQ family of DNA helicases. Such homology does not necessarily mean that WRN encodes an active helicase. For example, the Saccharomyces cerevisiae RAD26 gene protein7 and the human transcription-repair coupling factor CSB (Cockayne syndrome B)8 are highly homologous to known helicases, yet neither encodes an active helicase. Moreover, the Bloom's syndrome gene (BLM)9, discovered before WRN, is also homologous to the RecQ family of DNA helicases, though we still await demonstration that it encodes an active helicase. Here we report that the WS protein does indeed catalyze DNA unwinding.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Epstein, C.J., Martin, G.M., Schultz, A.L. & Motulsky, A.G. Werner's syndrome: a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine 45, 177–221 (1966).
    Article CAS Google Scholar
  2. Goto, M., Miller, R.W., Ishikawa, Y. & Sugano, H. Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol. Biomark. Prev. 5, 239–246 (1996).
    CAS Google Scholar
  3. Martin, G.M., Sprague, C.A. & Epstein, C.J. Replicative life-span of cultivated human cells. Lab. Invest. 23, 86–92 (1970).
    CAS PubMed Google Scholar
  4. Salk, D., Au, K., Hoehn, H. & Martin, G.M. Cytogenetics of Werner's syndrome cultured skin fibroblasts: variegated translocation mosaicism. Cytogenet. Cell Genet. 30, 92–107 (1981).
    Article CAS Google Scholar
  5. Fukuchi, K., Martin, G.M. & Monnat, R.J., Jr., Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Natl. Acad. Sci. USA 86, 5893–5897 (1989).
    Article CAS Google Scholar
  6. Yu, C.-E. et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 (1996).
    Article CAS Google Scholar
  7. van Gool, A.J. et al. RAD26, the functional S. cerevisiae homolog of the Cockayne syndrome B gene ERCC6. EMBO J. 13, 5361–5369 (1994).
    Article CAS Google Scholar
  8. Selby, C.P. & Sancar, A. Structure and function of transcription-repair coupling factor. I. Structural domains and binding properties. J. Biol. Chem. 270, 4882–4889 (1995).
    Article CAS Google Scholar
  9. Ellis, N.A. et al. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 80, 655–666 (1995).
    Article Google Scholar
  10. Lanford, R. Expression of simian virus 40 T antigen in insect cells using a baculovirus vector. J. Virol. 167, 72–81 (1988).
    Article CAS Google Scholar
  11. Lohman, T.M. Helicase-catalyzed DNA unwinding. J. Biol. Chem. 268, 2269–2272 (1993).
    CAS PubMed Google Scholar
  12. Matson, S.W. Escherichia coli helicase II (uvrD gene product) translocates unidirectionally in a 3′to 5′ direction. J. Biol. Chem. 261, 10169–10175 (1986).
    CAS PubMed Google Scholar
  13. George, J.W., Brosh, R.M., Jr., & Matson, S.W. A dominant negative allele of the Escherichia coli uvrD gene encoding DNA helicase II. J. Mol. Biol. 235, 424–435 (1994).
    Article CAS Google Scholar
  14. Lu, J. et al. Human homologues of yeast helicase. Nature 383, 678–679 (1996).
    Article CAS Google Scholar
  15. Umezu, K., Nakayama, K. & Nakayama, H. Escherichia coli RecQ protein is a DNA helicase. Proc. Natl. Acad. Sci. USA 87, 5363–5367 (1990).
    Article CAS Google Scholar
  16. Sung, P. et al. Human xeroderma pigmentosum group D gene encodes a DNA helicase. Nature 365, 852–855 (1993).
    Article CAS Google Scholar
  17. Umezu, K. & Nakayama, H. RecQ DNA helicase of Escherichia coli. J. Mol. Biol. 230, 1145–1150 (1993).
    Article CAS Google Scholar
  18. Boehmer, P.E., Dodson, M.S. & Lehman, I.R. The herpes simplex virus type-1 origin binding protein. J. Biol. Chem. 268, 1220–1225 (1993).
    CAS PubMed Google Scholar
  19. 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 Google Scholar
  20. Kowalczykowski, S.C., Dixon, D.A., Eggleston, A.K., Lauder, S.D. & Rehrauer, W.M. Biochemistry of homologous recombination in Escherichia coli. Microbiol. Rev. 58, 401–465 (1994).
    CAS PubMed PubMed Central Google Scholar
  21. Watt, P.M., Louis, E.J., Borts, R.H. & Hickson, I.D. Sgs1: a eukaryotic homolog of E. coli RecQ that interacts with topoisomerase II in vivo and is required for faithful chromosome segregation. Cell 81, 253–260 (1995).
    Article CAS Google Scholar
  22. Gebhart, E. et al. Spontaneous and induced chromosomal instability in Werner syndrome. Hum. Genet. 80, 135–139 (1988).
    Article CAS Google Scholar
  23. Yu, C.-E. et al. Mutations in the consensus helicase domains of the Werner syndrome gene. Am. J. Hum. Genet. 60, 330–341 (1997).
    CAS PubMed PubMed Central Google Scholar
  24. Oshima, J. et al. Homozygous and compound heterozygous mutations at the Werner syndrome locus. Hum. Mol. Gen. 5, 1909–1913 (1996).
    Article CAS Google Scholar
  25. Courcelle, J., Carswell-Crumpton, C. & Hanawalt, P.C. recf and recR are required for the resumption of replication at DNA replication forks in Escherichia coli. Proc. Natl. Acad. Sci. USA 94, 3714–3719 (1997).
    Article CAS Google Scholar
  26. Poot, M., Hoehn, H., Runger, T.M. & Martin, G.M., Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines. Exp. Cell. Res. 202, 267–273 (1992).
    Article CAS Google Scholar
  27. Berenblum, I. & Chain, E. An improved method for the colorimetric determination of phosphate. Biochem. J. 32, 295–298 (1938).
    Article CAS Google Scholar

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Washington, Box 357705, Seattle, Washington, 98195-7705, USA
    Matthew D. Gray, Jiang-Cheng Shen, Ashwini S. Kamath-Loeb, A. Blank, Bryce L. Sopher, George M. Martin, Junko Oshima & Lawrence A. Loeb

Authors

  1. Matthew D. Gray
    You can also search for this author inPubMed Google Scholar
  2. Jiang-Cheng Shen
    You can also search for this author inPubMed Google Scholar
  3. Ashwini S. Kamath-Loeb
    You can also search for this author inPubMed Google Scholar
  4. A. Blank
    You can also search for this author inPubMed Google Scholar
  5. Bryce L. Sopher
    You can also search for this author inPubMed Google Scholar
  6. George M. Martin
    You can also search for this author inPubMed Google Scholar
  7. Junko Oshima
    You can also search for this author inPubMed Google Scholar
  8. Lawrence A. Loeb
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toLawrence A. Loeb.

Rights and permissions

About this article

Cite this article

Gray, M., Shen, JC., Kamath-Loeb, A. et al. The Werner syndrome protein is a DNA helicase.Nat Genet 17, 100–103 (1997). https://doi.org/10.1038/ng0997-100

Download citation

This article is cited by