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 involve...

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Bibliographic Details
Published in:Journal of biomolecular structure & dynamics 2012-01, Vol.30 (5), p.505-523
Main Authors: Tamjar, Jevgenia, Katorcha, Elizaveta, Popov, Alexander, Malinina, Lucy
Format: Article
Language:English
Subjects:
Base Pair Mismatch
Base Pairing
Base pairs
Base Sequence
Crystal structure
Crystallography, X-Ray
Genetic Diseases, Inborn
Genome
Genomes
Humans
Models, Molecular
Neurodegenerative Diseases - genetics
Nucleic Acid Conformation
Oligonucleotides
protein-bound and protein-free U·U and G·U mismatches
RNA crystal structure
RNA Interference
RNA, Double-Stranded - chemistry
RNA, Double-Stranded - genetics
RNA, Small Interfering
RNA-mediated interference
Transcription, Genetic
trinucleotide repeat diseases
Trinucleotide Repeat Expansion
trinucleotide repeat expansion diseases
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Summary: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.
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2012.687517