CGG repeats associated with fragile X chromosome form left-handed Z-DNA structure.
This work is a continuation of our effort to determine the structure responsible for expansion of the (CGG)(n) motif that results in fragile X chromosome syndrome. In our previous report, we demonstrated that the structure adopted by an oligonucleotide with this repeat sequence is not a quadruplex as was suggested by others. Here we demonstrate that (CGG) runs adopt another anomalous arrangement-a left-handed Z-DNA structure. The Z-DNA formation was induced by high salt and millimolar concentrations of Ni(2+) ions and likelihood of its formation increased with increasing number of repeats. In an oligonucleotide in which the CGG runs were interrupted by AGG triplets, as is observed in genomes of healthy individuals, the hairpin conformation was stabilized and Z-DNA formation was hindered. We show here that methylation of the (CGG) runs markedly stabilized Z-DNA formation. We hypothesize that rather than in the expansion process the Z-DNA may be formed by long, expanded (CGG) stretches that become hypermethylated; this would inhibit transcription resulting in disease.
Renčiuk
Daniel
D
Institute of Biophysics, v.v.i., Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Kypr
Jaroslav
J
Vorlíčková
Michaela
M
D001483:Base Sequence; D043283:Chromosome Fragile Sites / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D002942:Circular Dichroism; D043542:DNA, Z-Form / Q000737:chemistry* / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics; D006801:Humans; D009690:Nucleic Acid Conformation; D018911:Trinucleotide Repeats
D043542:DNA, Z-Form