Skip to main content
PMC home page
Genetics logoLink to Genetics
. 1999 Mar;151(3):1027–1039. doi: 10.1093/genetics/151.3.1027

Evolution of the RECQ family of helicases: A drosophila homolog, Dmblm, is similar to the human bloom syndrome gene.

K Kusano 1, M E Berres 1, W R Engels 1
PMCID: PMC1460517  PMID: 10049920

Abstract

Several eukaryotic homologs of the Escherichia coli RecQ DNA helicase have been found. These include the human BLM gene, whose mutation results in Bloom syndrome, and the human WRN gene, whose mutation leads to Werner syndrome resembling premature aging. We cloned a Drosophila melanogaster homolog of the RECQ helicase family, Dmblm (Drosophila melanogaster Bloom), which encodes a putative 1487-amino-acid protein. Phylogenetic and dot plot analyses for the RECQ family, including 10 eukaryotic and 3 prokaryotic genes, indicate Dmblm is most closely related to the Homo sapiens BLM gene, suggesting functional similarity. Also, we found that Dmblm cDNA partially rescued the sensitivity to methyl methanesulfonate of Saccharomyces cerevisiae sgs1 mutant, demonstrating the presence of a functional similarity between Dmblm and SGS1. Our analyses identify four possible subfamilies in the RECQ family: (1) the BLM subgroup (H. sapiens Bloom, D. melanogaster Dmblm, and Caenorhabditis elegans T04A11.6); (2) the yeast RECQ subgroup (S. cerevisiae SGS1 and Schizosaccharomyces pombe rqh1/rad12); (3) the RECQL/Q1 subgroup (H. sapiens RECQL/Q1 and C. elegans K02F3.1); and (4) the WRN subgroup (H. sapiens Werner and C. elegans F18C5.2). This result may indicate that metazoans hold at least three RECQ genes, each of which may have a different function, and that multiple RECQ genes diverged with the generation of multicellular organisms. We propose that invertebrates such as nematodes and insects are useful as model systems of human genetic diseases.

Full Text

The Full Text of this article is available as a PDF (528.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bennett R. J., Sharp J. A., Wang J. C. Purification and characterization of the Sgs1 DNA helicase activity of Saccharomyces cerevisiae. J Biol Chem. 1998 Apr 17;273(16):9644–9650. doi: 10.1074/jbc.273.16.9644. [DOI] [PubMed] [Google Scholar]
  2. Davey S., Han C. S., Ramer S. A., Klassen J. C., Jacobson A., Eisenberger A., Hopkins K. M., Lieberman H. B., Freyer G. A. Fission yeast rad12+ regulates cell cycle checkpoint control and is homologous to the Bloom's syndrome disease gene. Mol Cell Biol. 1998 May;18(5):2721–2728. doi: 10.1128/mcb.18.5.2721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Eisen J. A., Sweder K. S., Hanawalt P. C. Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions. Nucleic Acids Res. 1995 Jul 25;23(14):2715–2723. doi: 10.1093/nar/23.14.2715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ellis N. A., Groden J., Ye T. Z., Straughen J., Lennon D. J., Ciocci S., Proytcheva M., German J. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell. 1995 Nov 17;83(4):655–666. doi: 10.1016/0092-8674(95)90105-1. [DOI] [PubMed] [Google Scholar]
  5. Fishel R., Lescoe M. K., Rao M. R., Copeland N. G., Jenkins N. A., Garber J., Kane M., Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993 Dec 3;75(5):1027–1038. doi: 10.1016/0092-8674(93)90546-3. [DOI] [PubMed] [Google Scholar]
  6. Fleischmann R. D., Adams M. D., White O., Clayton R. A., Kirkness E. F., Kerlavage A. R., Bult C. J., Tomb J. F., Dougherty B. A., Merrick J. M. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science. 1995 Jul 28;269(5223):496–512. doi: 10.1126/science.7542800. [DOI] [PubMed] [Google Scholar]
  7. Fryxell K. J. The coevolution of gene family trees. Trends Genet. 1996 Sep;12(9):364–369. doi: 10.1016/s0168-9525(96)80020-5. [DOI] [PubMed] [Google Scholar]
  8. Fujiwara Y., Higashikawa T., Tatsumi M. A retarded rate of DNA replication and normal level of DNA repair in Werner's syndrome fibroblasts in culture. J Cell Physiol. 1977 Sep;92(3):365–374. doi: 10.1002/jcp.1040920305. [DOI] [PubMed] [Google Scholar]
  9. 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. 1994 Dec;14(12):8391–8398. doi: 10.1128/mcb.14.12.8391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gebhart E., Bauer R., Raub U., Schinzel M., Ruprecht K. W., Jonas J. B. Spontaneous and induced chromosomal instability in Werner syndrome. Hum Genet. 1988 Oct;80(2):135–139. doi: 10.1007/BF00702855. [DOI] [PubMed] [Google Scholar]
  11. German J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore) 1993 Nov;72(6):393–406. [PubMed] [Google Scholar]
  12. Gorbalenya A. E., Koonin E. V., Donchenko A. P., Blinov V. M. Two related superfamilies of putative helicases involved in replication, recombination, repair and expression of DNA and RNA genomes. Nucleic Acids Res. 1989 Jun 26;17(12):4713–4730. doi: 10.1093/nar/17.12.4713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gray M. D., Shen J. C., Kamath-Loeb A. S., Blank A., Sopher B. L., Martin G. M., Oshima J., Loeb L. A. The Werner syndrome protein is a DNA helicase. Nat Genet. 1997 Sep;17(1):100–103. doi: 10.1038/ng0997-100. [DOI] [PubMed] [Google Scholar]
  14. Hanada K., Ukita T., Kohno Y., Saito K., Kato J., Ikeda H. RecQ DNA helicase is a suppressor of illegitimate recombination in Escherichia coli. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3860–3865. doi: 10.1073/pnas.94.8.3860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hartl D. L., Nurminsky D. I., Jones R. W., Lozovskaya E. R. Genome structure and evolution in Drosophila: applications of the framework P1 map. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6824–6829. doi: 10.1073/pnas.91.15.6824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Heartlein M. W., Tsuji H., Latt S. A. 5-Bromodeoxyuridine-dependent increase in sister chromatid exchange formation in Bloom's syndrome is associated with reduction in topoisomerase II activity. Exp Cell Res. 1987 Mar;169(1):245–254. doi: 10.1016/0014-4827(87)90242-4. [DOI] [PubMed] [Google Scholar]
  17. Henikoff S., Henikoff J. G. Position-based sequence weights. J Mol Biol. 1994 Nov 4;243(4):574–578. doi: 10.1016/0022-2836(94)90032-9. [DOI] [PubMed] [Google Scholar]
  18. Higgins D. G., Bleasby A. J., Fuchs R. CLUSTAL V: improved software for multiple sequence alignment. Comput Appl Biosci. 1992 Apr;8(2):189–191. doi: 10.1093/bioinformatics/8.2.189. [DOI] [PubMed] [Google Scholar]
  19. Hillis D. M., Huelsenbeck J. P. Signal, noise, and reliability in molecular phylogenetic analyses. J Hered. 1992 May-Jun;83(3):189–195. doi: 10.1093/oxfordjournals.jhered.a111190. [DOI] [PubMed] [Google Scholar]
  20. Huelsenbeck J. P., Rannala B. Phylogenetic methods come of age: testing hypotheses in an evolutionary context. Science. 1997 Apr 11;276(5310):227–232. doi: 10.1126/science.276.5310.227. [DOI] [PubMed] [Google Scholar]
  21. Imamura O., Ichikawa K., Yamabe Y., Goto M., Sugawara M., Furuichi Y. Cloning of a mouse homologue of the human Werner syndrome gene and assignment to 8A4 by fluorescence in situ hybridization. Genomics. 1997 Apr 15;41(2):298–300. doi: 10.1006/geno.1997.4661. [DOI] [PubMed] [Google Scholar]
  22. Irino N., Nakayama K., Nakayama H. The recQ gene of Escherichia coli K12: primary structure and evidence for SOS regulation. Mol Gen Genet. 1986 Nov;205(2):298–304. doi: 10.1007/BF00430442. [DOI] [PubMed] [Google Scholar]
  23. Ishizaki K., Yagi T., Inoue M., Nikaido O., Takebe H. DNA repair in Bloom's syndrome fibroblasts after UV irradiation or treatment with mitomycin C. Mutat Res. 1981 Jan;80(1):213–219. doi: 10.1016/0027-5107(81)90189-5. [DOI] [PubMed] [Google Scholar]
  24. Kaneko H., Orii K. O., Matsui E., Shimozawa N., Fukao T., Matsumoto T., Shimamoto A., Furuichi Y., Hayakawa S., Kasahara K. BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal. Biochem Biophys Res Commun. 1997 Nov 17;240(2):348–353. doi: 10.1006/bbrc.1997.7648. [DOI] [PubMed] [Google Scholar]
  25. Karow J. K., Chakraverty R. K., Hickson I. D. The Bloom's syndrome gene product is a 3'-5' DNA helicase. J Biol Chem. 1997 Dec 5;272(49):30611–30614. doi: 10.1074/jbc.272.49.30611. [DOI] [PubMed] [Google Scholar]
  26. Krepinsky A. B., Heddle J. A., German J. Sensitivity of Bloom's syndrome lymphocytes to ethyl methanesulfonate. Hum Genet. 1979;50(2):151–156. doi: 10.1007/BF00390236. [DOI] [PubMed] [Google Scholar]
  27. Kurihara T., Inoue M., Tatsumi K. Hypersensitivity of Bloom's syndrome fibroblasts to N-ethyl-N-nitrosourea. Mutat Res. 1987 Sep;184(2):147–151. doi: 10.1016/0167-8817(87)90071-x. [DOI] [PubMed] [Google Scholar]
  28. Kusano K., Sunohara Y., Takahashi N., Yoshikura H., Kobayashi I. DNA double-strand break repair: genetic determinants of flanking crossing-over. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1173–1177. doi: 10.1073/pnas.91.3.1173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lovett S. T., Sutera V. A., Jr Suppression of recJ exonuclease mutants of Escherichia coli by alterations in DNA helicases II (uvrD) and IV (helD). Genetics. 1995 May;140(1):27–45. doi: 10.1093/genetics/140.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lu J., Mullen J. R., Brill S. J., Kleff S., Romeo A. M., Sternglanz R. Human homologues of yeast helicase. Nature. 1996 Oct 24;383(6602):678–679. doi: 10.1038/383678a0. [DOI] [PubMed] [Google Scholar]
  31. Mount S. M., Burks C., Hertz G., Stormo G. D., White O., Fields C. Splicing signals in Drosophila: intron size, information content, and consensus sequences. Nucleic Acids Res. 1992 Aug 25;20(16):4255–4262. doi: 10.1093/nar/20.16.4255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Murray J. M., Lindsay H. D., Munday C. A., Carr A. M. Role of Schizosaccharomyces pombe RecQ homolog, recombination, and checkpoint genes in UV damage tolerance. Mol Cell Biol. 1997 Dec;17(12):6868–6875. doi: 10.1128/mcb.17.12.6868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Muse S. V., Gaut B. S. A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome. Mol Biol Evol. 1994 Sep;11(5):715–724. doi: 10.1093/oxfordjournals.molbev.a040152. [DOI] [PubMed] [Google Scholar]
  34. Mushegian A. R., Bassett D. E., Jr, Boguski M. S., Bork P., Koonin E. V. Positionally cloned human disease genes: patterns of evolutionary conservation and functional motifs. Proc Natl Acad Sci U S A. 1997 May 27;94(11):5831–5836. doi: 10.1073/pnas.94.11.5831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nassif N., Engels W. DNA homology requirements for mitotic gap repair in Drosophila. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1262–1266. doi: 10.1073/pnas.90.4.1262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ogburn C. E., Oshima J., Poot M., Chen R., Hunt K. E., Gollahon K. A., Rabinovitch P. S., Martin G. M. An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants. Hum Genet. 1997 Dec;101(2):121–125. doi: 10.1007/s004390050599. [DOI] [PubMed] [Google Scholar]
  37. Puranam K. L., Blackshear P. J. Cloning and characterization of RECQL, a potential human homologue of the Escherichia coli DNA helicase RecQ. J Biol Chem. 1994 Nov 25;269(47):29838–29845. [PubMed] [Google Scholar]
  38. Salk D., Au K., Hoehn H., Stenchever M. R., Martin G. M. Evidence of clonal attenuation, clonal succession, and clonal expansion in mass cultures of aging Werner's syndrome skin fibroblasts. Cytogenet Cell Genet. 1981;30(2):108–117. doi: 10.1159/000131597. [DOI] [PubMed] [Google Scholar]
  39. Scappaticci S., Cerimele D., Fraccaro M. Clonal structural chromosomal rearrangements in primary fibroblast cultures and in lymphocytes of patients with Werner's Syndrome. Hum Genet. 1982;62(1):16–24. doi: 10.1007/BF00295599. [DOI] [PubMed] [Google Scholar]
  40. Seki M., Miyazawa H., Tada S., Yanagisawa J., Yamaoka T., Hoshino S., Ozawa K., Eki T., Nogami M., Okumura K. Molecular cloning of cDNA encoding human DNA helicase Q1 which has homology to Escherichia coli Rec Q helicase and localization of the gene at chromosome 12p12. Nucleic Acids Res. 1994 Nov 11;22(22):4566–4573. doi: 10.1093/nar/22.22.4566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Seki M., Yanagisawa J., Kohda T., Sonoyama T., Ui M., Enomoto T. Purification of two DNA-dependent adenosinetriphosphatases having DNA helicase activity from HeLa cells and comparison of the properties of the two enzymes. J Biochem. 1994 Mar;115(3):523–531. doi: 10.1093/oxfordjournals.jbchem.a124369. [DOI] [PubMed] [Google Scholar]
  42. 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. 1998 Jun 15;26(12):2879–2885. doi: 10.1093/nar/26.12.2879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Shulman M. J., Collins C., Connor A., Read L. R., Baker M. D. Interchromosomal recombination is suppressed in mammalian somatic cells. EMBO J. 1995 Aug 15;14(16):4102–4107. doi: 10.1002/j.1460-2075.1995.tb00082.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sikorski R. S., Hieter P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics. 1989 May;122(1):19–27. doi: 10.1093/genetics/122.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sinclair D. A., Mills K., Guarente L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science. 1997 Aug 29;277(5330):1313–1316. doi: 10.1126/science.277.5330.1313. [DOI] [PubMed] [Google Scholar]
  46. Sorokin A., Azevedo V., Zumstein E., Galleron N., Ehrlich S. D., Serror P. Sequence analysis of the Bacillus subtilis chromosome region between the serA and kdg loci cloned in a yeast artificial chromosome. Microbiology. 1996 Aug;142(Pt 8):2005–2016. doi: 10.1099/13500872-142-8-2005. [DOI] [PubMed] [Google Scholar]
  47. Sorokin A., Zumstein E., Azevedo V., Ehrlich S. D., Serror P. The organization of the Bacillus subtilis 168 chromosome region between the spoVA and serA genetic loci, based on sequence data. Mol Microbiol. 1993 Oct;10(2):385–395. doi: 10.1111/j.1365-2958.1993.tb02670.x. [DOI] [PubMed] [Google Scholar]
  48. Stewart E., Chapman C. R., Al-Khodairy F., Carr A. M., Enoch T. rqh1+, a fission yeast gene related to the Bloom's and Werner's syndrome genes, is required for reversible S phase arrest. EMBO J. 1997 May 15;16(10):2682–2692. doi: 10.1093/emboj/16.10.2682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sullivan J., Holsinger K. E., Simon C. The effect of topology on estimates of among-site rate variation. J Mol Evol. 1996 Feb;42(2):308–312. doi: 10.1007/BF02198857. [DOI] [PubMed] [Google Scholar]
  50. Suzuki N., Shimamoto A., Imamura O., Kuromitsu J., Kitao S., Goto M., Furuichi Y. DNA helicase activity in Werner's syndrome gene product synthesized in a baculovirus system. Nucleic Acids Res. 1997 Aug 1;25(15):2973–2978. doi: 10.1093/nar/25.15.2973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Thorne J. L., Kishino H., Felsenstein J. An evolutionary model for maximum likelihood alignment of DNA sequences. J Mol Evol. 1991 Aug;33(2):114–124. doi: 10.1007/BF02193625. [DOI] [PubMed] [Google Scholar]
  52. Thorne J. L., Kishino H., Felsenstein J. Inching toward reality: an improved likelihood model of sequence evolution. J Mol Evol. 1992 Jan;34(1):3–16. doi: 10.1007/BF00163848. [DOI] [PubMed] [Google Scholar]
  53. Thorne J. L., Kishino H. Freeing phylogenies from artifacts of alignment. Mol Biol Evol. 1992 Nov;9(6):1148–1162. doi: 10.1093/oxfordjournals.molbev.a040783. [DOI] [PubMed] [Google Scholar]
  54. Uzzell T., Corbin K. W. Fitting discrete probability distributions to evolutionary events. Science. 1971 Jun 11;172(3988):1089–1096. doi: 10.1126/science.172.3988.1089. [DOI] [PubMed] [Google Scholar]
  55. Watt P. M., Hickson I. D., Borts R. H., Louis E. J. SGS1, a homologue of the Bloom's and Werner's syndrome genes, is required for maintenance of genome stability in Saccharomyces cerevisiae. Genetics. 1996 Nov;144(3):935–945. doi: 10.1093/genetics/144.3.935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Watt P. M., Hickson I. D. Failure to unwind causes cancer. Genome stability. Curr Biol. 1996 Mar 1;6(3):265–267. doi: 10.1016/s0960-9822(02)00474-8. [DOI] [PubMed] [Google Scholar]
  57. 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. 1995 Apr 21;81(2):253–260. doi: 10.1016/0092-8674(95)90335-6. [DOI] [PubMed] [Google Scholar]
  58. Wilson R., Ainscough R., Anderson K., Baynes C., Berks M., Bonfield J., Burton J., Connell M., Copsey T., Cooper J. 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature. 1994 Mar 3;368(6466):32–38. doi: 10.1038/368032a0. [DOI] [PubMed] [Google Scholar]
  59. Yamagata K., Kato J., Shimamoto A., Goto M., Furuichi Y., Ikeda H. Bloom's and Werner's syndrome genes suppress hyperrecombination in yeast sgs1 mutant: implication for genomic instability in human diseases. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8733–8738. doi: 10.1073/pnas.95.15.8733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yan H., Chen C. Y., Kobayashi R., Newport J. Replication focus-forming activity 1 and the Werner syndrome gene product. Nat Genet. 1998 Aug;19(4):375–378. doi: 10.1038/1263. [DOI] [PubMed] [Google Scholar]
  61. Yang Z. Estimating the pattern of nucleotide substitution. J Mol Evol. 1994 Jul;39(1):105–111. doi: 10.1007/BF00178256. [DOI] [PubMed] [Google Scholar]
  62. Yu C. E., Oshima J., Fu Y. H., Wijsman E. M., Hisama F., Alisch R., Matthews S., Nakura J., Miki T., Ouais S. Positional cloning of the Werner's syndrome gene. Science. 1996 Apr 12;272(5259):258–262. doi: 10.1126/science.272.5259.258. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES