Struktura a patogeneza chorób związanych z ekspansją powtórzeń CNG

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Struktura a patogeneza chorób związanych z ekspansją powtórzeń CNG

Journal Title: Wiadomości Chemiczne - Year 2014, Vol 68, Issue 5

Abstract

CNG repeats (N stands for one of the four natural nucleotides) are a special class of microsatellite sequences of the human genome. They are most often found in exons, in their coding parts as well as in the 5’ or 3’ untranslated regions. Characteristic frequencies of their occurrence within the different parts of the genes suggest that they play a functional role. The number of CNG repeats in a block is usually below 30 but it can undergo abnormal expansion leading to the development of one of approximately 20 neurological diseases known as TREDs (Triplet Repeat Expansion Disorders). One model of pathogenesis proposes that the toxic factor is mRNA containing an expanded run of CNG repeats. The anomaly results in aberrant alternative splicing and/or accumulation of the RNA in the cell nucleus, followed by a sequestration of important regulatory proteins and formation of RNA/ protein aggregates known as nuclear foci. This is accompanied by a deregulation of vital cellular processes. In this paper we have focused on crystallographic studies of RNA oligomers with embedded CNG repeats. We describe briefly diseases associated with each type of repeat and present the crystal structures. All the CNG repeats form stable “hairpins” consisting of a small apical loop and a long double-stranded stem, in which the non-canonical N-N pairs are flanked by the standard C-G and G-C pairs. All CNG repeats form duplexes of type A, characteristic of RNA, but with local deviations from the typical geometry (Fig. 1). The duplexes are stabilised by the strong C-G and G-C Watson-Crick interactions, while the N-N pairs are accommodated within the helical context, each in a characteristic way (Fig. 2). The U-U pairs tend to form just one hydrogen bond, instead of two observed in other contexts. The interactions within the C-C pairs are even weaker, via one very weak hydrogen bond or none. On the other hand, accommodation of the bulky A-A pairs involves pushing the purine rings towards the major groove while in the G-G pairs one of the guanosine residues flips to a syn conformation. The unrealised hydrogen-bonding potential of the N-N pairs is externalised into the major and the minor grooves and can be assessed through interactions with ordered water molecules and other small ligands. The N-N pairs are associated with local distortions of the A-helix (Fig. 1). All the CNG repeats show a characteristic striped pattern of surface electrostatic potential in the minor groove (Fig. 3). Assessment of the different CNG structures allows us to identify the characteristic and the common features (Tab. 1).

Authors and Affiliations

Agnieszka Kiliszek, Wojciech Rypniewski

Keywords

struktura krystalograficzna RNA TREDs powtórzenia CNG

EP ID EP585256
DOI -
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