5'-UTR RNA G-quadruplexes: translation regulation and targeting

Abstract

RNA structures in the untranslated regions (UTRs) of mRNAs influence post-transcriptional regulation of gene expression. Much of the knowledge in this area depends on canonical double-stranded RNA elements. There has been considerable recent advancement of our understanding of guanine(G)-rich nucleic acids sequences that form four-stranded structures, called G-quadruplexes. While much of the research has been focused on DNA G-quadruplexes, there has recently been a rapid emergence of interest in RNA G-quadruplexes, particularly in the 5′-UTRs of mRNAs. Collectively, these studies suggest that RNA G-quadruplexes exist in the 5′-UTRs of many genes, including genes of clinical interest, and that such structural elements can influence translation. This review features the progresses in the study of 5′-UTR RNA G-quadruplex-mediated translational control. It covers computational analysis, cell-free, cell-based and chemical biology studies that have sought to elucidate the roles of RNA G-quadruplexes in both cap-dependent and -independent regulation of mRNA translation. We also discuss protein trans-acting factors that have been implicated and the evidence that such RNA motifs have potential as small molecule target. Finally, we close the review with a perspective on the future challenges in the field of 5′-UTR RNA G-quadruplex-mediated translation regulation.

ChemR23, the Receptor for Chemerin and Resolvin E1, Is Expressed and Functional on M1 but Not on M2 Macrophages

“…All differentially spliced exons are noncoding and have no effect on the final size and sequence of the protein. However, such differential splicing and the presence of various mRNA isoforms may represent an additional way of ChemR23 regulation, because sequence characteristics within the 59 UTR have an essential impact on the differential regulation of translation efficiency and mRNA stability (45).…”

558 RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

“…We noticed that in many instances the 5′UTR motifs coincided with computationally predicted G-quadruplex (GQ) structures 29 . For example 51% of the 12-mer (CGG) 4 sequences and 43% of the most common 9-mer localized precisely to the GQ structuresthe ADAM10 5′UTR provides an example (Figure 4a/b, Extended Data Fig.…”

“…Besides 5′UTR length, these included a 12-mer (CGG) 4 motif, additional 9-mer motifs, and computationally predicted GQ structures that correspond to the motif. RNA GQs are energetically favourable/stable RNA structures made from at least two stacks of four guanosines with non-Watson-Crick interactions (Hoogsteen hydrogen bonds) with intervening linker nucleotides 29 . The minimum number is twelve nucleotides, e.g.…”

Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

“…46,47 They can be formed both by DNA and RNA, and they are abundant at telomeric DNA, gene promoters, and mRNA 5 0 -UTRs. 48,49 The importance of these structures in regulating several cellular processes at the translational and posttranslational levels is emerging clearly and a number of proteins have been shown to interact with and to stabilize or destabilize the G-quadruplex fold. 50 A well-characterized G-quadruplex sequence is present at the nuclease hypersensitive element III (NHE III ) of the c-MYC promoter, and regulates up to 90% of c-MYC gene transcription.…”