Structural dynamics of double-helical RNAs composed of CUG/CUG- and CUG/CGG-repeats.
Human genetic trinucleotide repeat expansion diseases (TREDs) are characterized by triplet repeat expansions, most frequently found as CNG-tracts in genome. At RNA level, such expansions suggestively result in formation of double-helical hairpins that become a potential source for small RNAs involved in RNA interference (RNAi). Here, we present three crystal structures of RNA fragments composed of triplet repeats CUG and CGG/CUG, as well as two crystal structures of same triplets in a protein-bound state. We show that both 20mer pG(CUG)(6)C and 19mer pGG(CGG)(3)(CUG)(2)CC form A-RNA duplexes, in which U·U or G·U mismatches are flanked/stabilized by two consecutive Watson-Crick G·C base pairs resulting in high-stacking GpC steps in every third position of the duplex. Despite interruption of this regularity in another 19mer, p(CGG)(3)C(CUG)(3), the oligonucleotide still forms regular double-helical structure, characterized, however, by 12 bp (rather than 11 bp) per turn. Analysis of newly determined molecular structures reveals the dynamic aspects of U·U and G·U mismatching within CNG-repetitive A-RNA and in a protein-bound state, as well as identifies an additional mode of U·U pairing essential for its dynamics and sheds the light on possible role of regularity of trinucleotide repeats for double-helical RNA structure. Findings are important for understanding the structural behavior of CNG-repetitive RNA double helices implicated in TREDs.
Structural Biology Unit, CIC bioGUNE, Technology Park of Bizkaia, Derio-Bilbao 48160, Spain.
Jevgenia
J
Tamjar
Elizaveta
E
Katorcha
Alexander
A
Popov
Lucy
L
Malinina
D020137:Base Pair Mismatch; D020029:Base Pairing; D001483:Base Sequence; D018360:Crystallography, X-Ray; D030342:Genetic Diseases, Inborn; D016678:Genome; D006801:Humans; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000235:genetics; D009690:Nucleic Acid Conformation; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000737:chemistry* / Q000235:genetics; D034741:RNA, Small Interfering; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion
D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering