Structures of RNA repeats associated with neurological diseases

Abstract

All RNA molecules possess a 'propensity' to fold into complex secondary and tertiary structures. Although they are composed of only four types of nucleotides, they show an enormous structural richness which reflects their diverse functions in the cell. However, in some cases the folding of RNA can have deleterious consequences. Aberrantly expanded, repeated RNA sequences can exhibit gain-of-function abnormalities and become pathogenic, giving rise to many incurable neurological diseases. Most RNA repeats form long hairpin structures whose stem consists of noncanonical base pairs interspersed among Watson-Crick pairs. The expanded hairpins have an ability to sequester important proteins and form insoluble nuclear foci. The RNA pathology, common to many repeat disorders, has drawn attention to the structures of the RNA repeats. In this review, we summarize secondary structure probing and crystallographic studies of disease-related RNA repeat sequences. We discuss the unique structural features which can contribute to the pathogenic properties of the repeated runs. In addition, we present the newest reports concerning structural data linked to therapeutic approaches. WIREs RNA 2017, 8:e1412. doi: 10.1002/wrna.1412 For further resources related to this article, please visit the WIREs website.

Retroviral-like determinants and functions required for dimerization of Ty1 retrotransposon RNA

“…The 3D structure model of PAL1-PAL2 extended duplex suggests formation of non-canonical C-U intermolecular base-pairs involving U21 and C22 residues. Non-canonical C-U base pairs were identified in several biologically important RNAs and RNA duplexes containing the C-U base pairs can be considered similar to typical A-RNA helices [71,72]. The preservation of continuous stacking contributes significantly to the stability of RNA folds and minimizes the exposure of hydrophobic base surfaces to polar solvent.…”

Nanopore electric snapshots of an RNA tertiary folding pathway

“…The improved system has the potential to study a variety of disease-relevant RNA and DNA tertiary structures, from hairpins 58 and PKs 59 to kissing-loops 60 and G-quadruplexes 61 , and RNA-based interactions, from microRNA–target RNA interactions to ligand–RNA interactions, such as RNA repeats 62 and riboswitches 63 . In addition to mutant construction, modified nucleotides can be introduced to detect chemical-specific folding procedures in the nanopore.…”

A potential role of extended simple sequence repeats in competing endogenous RNA crosstalk

“…Some of the transcribed SSR tracts are predicted to form specific secondary structures such as hairpins and quadruplexes [16]. In case of diseases, expanded tracts of CAG, CUG, CGG, CCUG repeats are predicted to form long stable hairpins which are considered factors responsible for gain-offunction RNA toxicity [17,18]. One of the interesting examples that we found is circRNA hsa_circ_0055538 which has closely located 20 CGG repeat tracts (composed of 5, 13, 10, 10, 5, 7, 12, 11, 9, 19, 10, 10, 7, 8, 9, 11, 6, 12, 13 and 7 repeats) separated by short GC-rich sequences that are predicted to form multiple hairpins ( Supplementary Fig.…”