title: Interruption of the fragile X syndrome expanded sequence d(CGG)(n) by interspersed d(AGG) trinucleotides diminishes the formation and stability of d(CGG)(n) tetrahelical structures.
abstract: Fragile X syndrome is caused by expansion of a d(CGG) trinucleotide repeat sequence in the 5' untranslated region of the first exon of the FMR1 gene. Repeat expansion is thought to be instigated by formation of d(CGG)(n)secondary structures. Stable FMR1 d(CGG)(n)runs in normal individuals consist of 6-52 d(CGG) repeats that are interrupted every 9-11 triplets by a single d(AGG) trinucleotide. By contrast, individuals having fragile X syndrome premutation or full mutation present >54-200 or >200-2000 monotonous d(CGG) repeats, respectively. Here we show that the presence of interspersed d(AGG) triplets diminished in vitro formation of bimolecular tetrahelical structures of d(CGG)(18)oligomers. Tetraplex structures formed by d(CGG)(n)oligomers containing d(AGG) interspersions had lower thermal stability. In addition, tetraplex structures of d(CGG)(18)oligomers interspersed by d(AGG) triplets were unwound by human Werner syndrome DNA helicase at rates and to an extent that exceeded the unwinding of tetraplex form consisting of monotonous d(CGG)(18). Diminished formation and stability of tetraplex structures of d(AGG)-containing FMR1 d(CGG)(2-50)tracts might restrict their expansion in normal individuals.
authors.affiliation: Unit of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, PO Box 9649, Haifa 31096, Israel.
authors.forename: P
authors.initials: P
authors.lastname: Weisman-Shomer
authors.forename: E
authors.initials: E
authors.lastname: Cohen
authors.forename: M
authors.initials: M
authors.lastname: Fry
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D004265:DNA Helicases / Q000378:metabolism; D005090:Exodeoxyribonucleases; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018598:Minisatellite Repeats; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009690:Nucleic Acid Conformation; D016601:RNA-Binding Proteins; D053484:RecQ Helicases; D018911:Trinucleotide Repeats; D000071657:Werner Syndrome Helicase
chemical_list: D004247:DNA; D004265:DNA Helicases; D005090:Exodeoxyribonucleases; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C497683:FMR1 protein, human; C098785:WRN protein, human