Identification of consensus binding sites clarifies FMRP binding determinants

Anderson, Bart R.; Chopra, Pankaj; Suhl, Joshua A.; Warren, Stephen T.; Bassell, Gary J.

doi:10.1093/nar/gkw593

Cited by 53 publications

(51 citation statements)

References 38 publications

(84 reference statements)

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“…Scanning inhibition is thought to be further increased by recruitment of RG4-stabilizing proteins 63,66 such as fragile X mental retardation protein (FMRP) 73 , which binds to many RG4-harbouring mRNAs 74,75 (FIG. 2b).…”

Section: ′ Utr Structures In Ribosome Scanningmentioning

confidence: 99%

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Leppek

Das

Barna

2017

Nat Rev Mol Cell Biol

707

645

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RNA molecules can fold into intricate shapes that can provide an additional layer of control of gene expression beyond that of their sequence. In this Review, we discuss the current mechanistic understanding of structures in 5′ untranslated regions (UTRs) of eukaryotic mRNAs and the emerging methodologies used to explore them. These structures may regulate cap-dependent translation initiation through helicase-mediated remodelling of RNA structures and higher-order RNA interactions, as well as cap-independent translation initiation through internal ribosome entry sites (IRESs), mRNA modifications and other specialized translation pathways. We discuss known 5′ UTR RNA structures and how new structure probing technologies coupled with prospective validation, particularly compensatory mutagenesis, are likely to identify classes of structured RNA elements that shape post-transcriptional control of gene expression and the development of multicellular organisms.

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Section: ′ Utr Structures In Ribosome Scanningmentioning

confidence: 99%

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Leppek

Das

Barna

2017

Nat Rev Mol Cell Biol

707

645

View full text Add to dashboard Cite

show abstract

“…Dramatic changes in polysome-association of these mRNAs were observed in the absence of FMRP, indicating that translational dysregulation of these mRNAs may underpin FXS 123 . Recently, this was redefined by large-scale CLIP (crosslinking immunoprecipitation) studies, where 34,218 consensus FMRP binding sites in 3,703 genes were identified 124 . It was reported that a G4 sequence in the FMR1 mRNA provides the docking site for FMRP.…”

Section: Fmrpmentioning

confidence: 99%

RNA G-quadruplexes and their potential regulatory roles in translation

et al. 2016

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DNA guanine (G)-rich 4-stranded helical nucleic acid structures called G-quadruplexes (G4), have been extensively studied during the last decades. However, emerging evidence reveals that 5′- and 3′-untranslated regions (5′- and 3′-UTRs) as well as open reading frames (ORFs) contain putative RNA G-quadruplexes. These stable secondary structures play key roles in telomere homeostasis and RNA metabolism including pre-mRNA splicing, polyadenylation, mRNA targeting and translation. Interestingly, multiple RNA binding proteins such as nucleolin, FMRP, DHX36, and Aven were identified to bind RNA G-quadruplexes. Moreover, accumulating reports suggest that RNA G-quadruplexes regulate translation in cap-dependent and -independent manner. Herein, we discuss potential roles of RNA G-quadruplexes and associated trans-acting factors in the regulation of mRNA translation.

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“…How FMRP recognizes and binds its functional targets is also not well understood. Several studies have reported transcript and RNA motif targets for FMRP in vitro and in vivo (Ascano et al, 2012;Brown et al, 2001;Darnell et al, 2001Darnell et al, , 2005aVasilyev et al, 2015), yet considerable disagreement among these studies remains about the identity of RNA sequences that interact with FMRP with high-affinity (Anderson et al, 2016). RNA G-quadruplex sequences have been repeatedly identified as binding targets of FMRP Schaeffer et al, 2001), but other studies have found that FMRP binds completely different short RNA motifs (Ray et al, 2013) while still others seem to show that FMRP displays almost no sequence specificity at all and instead binds all along the coding sequence of its target transcripts (Darnell et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

Goering

Hudish

Guzman

et al. 2019

Preprint

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The sorting of RNA molecules to distinct subcellular locations facilitates the activity of spatially restricted processes through local protein synthesis. This process affects thousands of transcripts yet precisely how these RNAs are trafficked to their destinations remains generally unclear. Here we have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these FMRP RNA localization targets contain a large enrichment of G-quadruplex sequences, particularly in their 3′ UTRs, suggesting that FMRP recognizes these sequences to promote the localization of transcripts that contain them. Fractionation of neurons derived from human Fragile X Syndrome patients revealed a high degree of conservation in the identity of FMRP localization targets between human and mouse as well as an enrichment of G-quadruplex sequences in human FMRP RNA localization targets. Using high-throughput RNA/protein interaction assays and single-molecule RNA FISH, we identified the RGG domain of FMRP as important for both interaction with G-quadruplex RNA sequences and the neuronal transport of G-quadruplex-containing transcripts. Finally, we used ribosome footprinting to identify translational regulatory targets of FMRP. The translational regulatory targets were not enriched for G-quadruplex sequences and were largely distinct from the RNA localization targets of FMRP, indicating that the two functions can be biochemically separated and are mediated through different target recognition mechanisms. These results establish a molecular mechanism underlying FMRP-mediated neuronal RNA localization and provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

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Identification of consensus binding sites clarifies FMRP binding determinants

Cited by 53 publications

References 38 publications

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

RNA G-quadruplexes and their potential regulatory roles in translation

FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

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