Skip to main content
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1995 Jun 11;23(11):1876–1881. doi: 10.1093/nar/23.11.1876

Compact structures of d(CNG)n oligonucleotides in solution and their possible relevance to fragile X and related human genetic diseases.

J E Mitchell 1, S F Newbury 1, J A McClellan 1
PMCID: PMC306957  PMID: 7596812

Abstract

We show that oligonucleotides of CNG tracts readily adopt compact DNA structures that move unusually fast on gels. Base composition does not explain this, and non-CNG triplets (including GNC) do not form such structures. Chemical probing and melting experiments suggest that the structures probably are not hairpins. Although both long and short tracts can adopt compact structures, the structure formed by longer tracts is more compact than that formed by shorter ones. We note the possibility that such structures may form in vivo, and be instrumental in normal and/or abnormal function of human genes.

Full text

PDF
1880

Images in this article

Selected References

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

  1. Bell M. V., Hirst M. C., Nakahori Y., MacKinnon R. N., Roche A., Flint T. J., Jacobs P. A., Tommerup N., Tranebjaerg L., Froster-Iskenius U. Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome. Cell. 1991 Feb 22;64(4):861–866. doi: 10.1016/0092-8674(91)90514-y. [DOI] [PubMed] [Google Scholar]
  2. Brook J. D., McCurrach M. E., Harley H. G., Buckler A. J., Church D., Aburatani H., Hunter K., Stanton V. P., Thirion J. P., Hudson T. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992 Feb 21;68(4):799–808. doi: 10.1016/0092-8674(92)90154-5. [DOI] [PubMed] [Google Scholar]
  3. Caskey C. T., Pizzuti A., Fu Y. H., Fenwick R. G., Jr, Nelson D. L. Triplet repeat mutations in human disease. Science. 1992 May 8;256(5058):784–789. doi: 10.1126/science.1589758. [DOI] [PubMed] [Google Scholar]
  4. Dolinnaya N. G., Braswell E. H., Fossella J. A., Klump H., Fresco J. R. Molecular and thermodynamic properties of d(A(+)-G)10, a single-stranded nucleic acid helix without paired or stacked bases. Biochemistry. 1993 Sep 28;32(38):10263–10270. doi: 10.1021/bi00089a049. [DOI] [PubMed] [Google Scholar]
  5. Fry M., Loeb L. A. The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4950–4954. doi: 10.1073/pnas.91.11.4950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fu Y. H., Kuhl D. P., Pizzuti A., Pieretti M., Sutcliffe J. S., Richards S., Verkerk A. J., Holden J. J., Fenwick R. G., Jr, Warren S. T. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991 Dec 20;67(6):1047–1058. doi: 10.1016/0092-8674(91)90283-5. [DOI] [PubMed] [Google Scholar]
  7. Fu Y. H., Pizzuti A., Fenwick R. G., Jr, King J., Rajnarayan S., Dunne P. W., Dubel J., Nasser G. A., Ashizawa T., de Jong P. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992 Mar 6;255(5049):1256–1258. doi: 10.1126/science.1546326. [DOI] [PubMed] [Google Scholar]
  8. Gehring K., Leroy J. L., Guéron M. A tetrameric DNA structure with protonated cytosine.cytosine base pairs. Nature. 1993 Jun 10;363(6429):561–565. doi: 10.1038/363561a0. [DOI] [PubMed] [Google Scholar]
  9. Greaves D. R., Patient R. K., Lilley D. M. Facile cruciform formation by an (A-T)34 sequence from a Xenopus globin gene. J Mol Biol. 1985 Oct 5;185(3):461–478. doi: 10.1016/0022-2836(85)90064-6. [DOI] [PubMed] [Google Scholar]
  10. Green H. Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell. 1993 Sep 24;74(6):955–956. doi: 10.1016/0092-8674(93)90718-6. [DOI] [PubMed] [Google Scholar]
  11. Heitz D., Rousseau F., Devys D., Saccone S., Abderrahim H., Le Paslier D., Cohen D., Vincent A., Toniolo D., Della Valle G. Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island. Science. 1991 Mar 8;251(4998):1236–1239. doi: 10.1126/science.2006411. [DOI] [PubMed] [Google Scholar]
  12. Knight S. J., Flannery A. V., Hirst M. C., Campbell L., Christodoulou Z., Phelps S. R., Pointon J., Middleton-Price H. R., Barnicoat A., Pembrey M. E. Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell. 1993 Jul 16;74(1):127–134. doi: 10.1016/0092-8674(93)90300-f. [DOI] [PubMed] [Google Scholar]
  13. Koide R., Ikeuchi T., Onodera O., Tanaka H., Igarashi S., Endo K., Takahashi H., Kondo R., Ishikawa A., Hayashi T. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994 Jan;6(1):9–13. doi: 10.1038/ng0194-9. [DOI] [PubMed] [Google Scholar]
  14. La Spada A. R., Wilson E. M., Lubahn D. B., Harding A. E., Fischbeck K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991 Jul 4;352(6330):77–79. doi: 10.1038/352077a0. [DOI] [PubMed] [Google Scholar]
  15. McClellan J. A., Boublíková P., Palecek E., Lilley D. M. Superhelical torsion in cellular DNA responds directly to environmental and genetic factors. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8373–8377. doi: 10.1073/pnas.87.21.8373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McClellan J. A., Lilley D. M. A two-state conformational equilibrium for alternating (A-T)n sequences in negatively supercoiled DNA. J Mol Biol. 1987 Oct 20;197(4):707–721. doi: 10.1016/0022-2836(87)90477-3. [DOI] [PubMed] [Google Scholar]
  17. McClellan J. A., Lilley D. M. Structural alteration in alternating adenine-thymine sequences in positively supercoiled DNA. J Mol Biol. 1991 May 20;219(2):145–149. doi: 10.1016/0022-2836(91)90555-k. [DOI] [PubMed] [Google Scholar]
  18. McClellan J. A., Palecek E., Lilley D. M. (A-T)n tracts embedded in random sequence DNA--formation of a structure which is chemically reactive and torsionally deformable. Nucleic Acids Res. 1986 Dec 9;14(23):9291–9309. doi: 10.1093/nar/14.23.9291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Morell V. The puzzle of the triple repeats. Science. 1993 Jun 4;260(5113):1422–1423. doi: 10.1126/science.8502986. [DOI] [PubMed] [Google Scholar]
  20. Nagafuchi S., Yanagisawa H., Sato K., Shirayama T., Ohsaki E., Bundo M., Takeda T., Tadokoro K., Kondo I., Murayama N. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet. 1994 Jan;6(1):14–18. doi: 10.1038/ng0194-14. [DOI] [PubMed] [Google Scholar]
  21. Newbury S. F., Smith N. H., Robinson E. C., Hiles I. D., Higgins C. F. Stabilization of translationally active mRNA by prokaryotic REP sequences. Cell. 1987 Jan 30;48(2):297–310. doi: 10.1016/0092-8674(87)90433-8. [DOI] [PubMed] [Google Scholar]
  22. Oberlé I., Rousseau F., Heitz D., Kretz C., Devys D., Hanauer A., Boué J., Bertheas M. F., Mandel J. L. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 1991 May 24;252(5009):1097–1102. doi: 10.1126/science.252.5009.1097. [DOI] [PubMed] [Google Scholar]
  23. Orr H. T., Chung M. Y., Banfi S., Kwiatkowski T. J., Jr, Servadio A., Beaudet A. L., McCall A. E., Duvick L. A., Ranum L. P., Zoghbi H. Y. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993 Jul;4(3):221–226. doi: 10.1038/ng0793-221. [DOI] [PubMed] [Google Scholar]
  24. Peck L. J., Wang J. C. Transcriptional block caused by a negative supercoiling induced structural change in an alternating CG sequence. Cell. 1985 Jan;40(1):129–137. doi: 10.1016/0092-8674(85)90316-2. [DOI] [PubMed] [Google Scholar]
  25. Pieretti M., Zhang F. P., Fu Y. H., Warren S. T., Oostra B. A., Caskey C. T., Nelson D. L. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991 Aug 23;66(4):817–822. doi: 10.1016/0092-8674(91)90125-i. [DOI] [PubMed] [Google Scholar]
  26. Reik W. Genomic imprinting and genetic disorders in man. Trends Genet. 1989 Oct;5(10):331–336. doi: 10.1016/0168-9525(89)90138-8. [DOI] [PubMed] [Google Scholar]
  27. Richards R. I., Holman K., Yu S., Sutherland G. R. Fragile X syndrome unstable element, p(CCG)n, and other simple tandem repeat sequences are binding sites for specific nuclear proteins. Hum Mol Genet. 1993 Sep;2(9):1429–1435. doi: 10.1093/hmg/2.9.1429. [DOI] [PubMed] [Google Scholar]
  28. Smith S. S., Laayoun A., Lingeman R. G., Baker D. J., Riley J. Hypermethylation of telomere-like foldbacks at codon 12 of the human c-Ha-ras gene and the trinucleotide repeat of the FMR-1 gene of fragile X. J Mol Biol. 1994 Oct 21;243(2):143–151. doi: 10.1006/jmbi.1994.1640. [DOI] [PubMed] [Google Scholar]
  29. Verheij C., Bakker C. E., de Graaff E., Keulemans J., Willemsen R., Verkerk A. J., Galjaard H., Reuser A. J., Hoogeveen A. T., Oostra B. A. Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature. 1993 Jun 24;363(6431):722–724. doi: 10.1038/363722a0. [DOI] [PubMed] [Google Scholar]
  30. Verkerk A. J., Pieretti M., Sutcliffe J. S., Fu Y. H., Kuhl D. P., Pizzuti A., Reiner O., Richards S., Victoria M. F., Zhang F. P. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991 May 31;65(5):905–914. doi: 10.1016/0092-8674(91)90397-h. [DOI] [PubMed] [Google Scholar]
  31. Wang Y. H., Amirhaeri S., Kang S., Wells R. D., Griffith J. D. Preferential nucleosome assembly at DNA triplet repeats from the myotonic dystrophy gene. Science. 1994 Jul 29;265(5172):669–671. doi: 10.1126/science.8036515. [DOI] [PubMed] [Google Scholar]
  32. Williamson J. R., Raghuraman M. K., Cech T. R. Monovalent cation-induced structure of telomeric DNA: the G-quartet model. Cell. 1989 Dec 1;59(5):871–880. doi: 10.1016/0092-8674(89)90610-7. [DOI] [PubMed] [Google Scholar]
  33. Yu S., Pritchard M., Kremer E., Lynch M., Nancarrow J., Baker E., Holman K., Mulley J. C., Warren S. T., Schlessinger D. Fragile X genotype characterized by an unstable region of DNA. Science. 1991 May 24;252(5009):1179–1181. doi: 10.1126/science.252.5009.1179. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES