Cited by 949RNA and protein synthesis mechanismsRNA Research and SplicingRNA modifications and cancer

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

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Leppek, Kathrin, Das, Rhiju, Barna, Maria·2018·Nature Reviews Molecular Cell Biology

Abstract

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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Crossref · 10.1038/nrm.2017.103

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  • Only 13% of human 5′ UTRs are shorter than 50 nt and thus covered by Optimus 5-Prime.

    “Because only 13% of human 5′ UTRs are shorter than 50 nt and thus covered by Optimus 5-Prime, we next asked whether the approach introduced here could be extended to longer 5′ UTRs.”

    From Human 5′ UTR design and variant effect prediction from a massively parallel translation assay (2019) · cites this paper as [45]

    The section ‘5′ UTRs as platforms for RNA structure’ (page unavailable) reports a median human 5′ UTR length of 218 nucleotides, supporting the general point that many are longer than 50 nt. It does not give the 13% figure or discuss which UTRs Optimus 5-Prime covers. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • Human 5′ UTR sequences vary in length from tens to thousands of nucleotides with a median length of 218 nt.

    “Human 5′ UTR sequences vary in length from tens to thousands of nucleotides with a median length of 218 nt44,45.”
  • Higher GC content and highly negative folding minimal free energy (ΔG) of 5′UTRs correlate with inhibition of translation.

    “In addition to greater length, the TPL sequence has a higher GC content and highly negative folding minimal free energy (ΔG), which correlates with inhibition of translation [4,7,45,46] (Table 1).”
  • Untranslated regions harbor regulatory elements that influence translational efficiency and mRNA stability within cells.

    “The untranslated regions harbor regulatory elements that influence translational efficiency and mRNA stability within cells [10,11].”
  • Shorter 5′UTRs are better for mRNA translation.

    “(iii) Shorter 5′UTRs may be used, as past research has indicated that this type of 5′UTR is better for mRNA translation (Leppek et al. 2018).”

    From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Leppek et al. 2018

    The section ‘5′ UTRs as platforms for RNA structure’ describes variation in UTR length but does not compare translation efficiency by length. ‘5′ UTR structures in ribosome scanning’ notes that some exceptionally short UTRs permit scanning-free initiation; it does not say shorter UTRs are generally better for translation. Searches for short UTRs and translational efficiency found no such comparison in our copy. (LLM, conf=0.70)

    Experimental — accuracy not yet measured

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Authors
Leppek, K., Das, R., & Barna, M.
Affiliations
Stanford University (US)
Corresponding author
  • Das, Rhiju
  • Barna, Maria
Venue
Nature Reviews Molecular Cell Biology
Published
2017-11-22
Volume
19
Issue
3
Pages
158-174
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
OpenAlex
W2770378609
Cited by
949
References
209
Citations by year
2026: 109 · 2025: 145 · 2024: 139 · 2023: 112 · 2022: 129 · 2021: 111 · 2020: 102 · 2019: 62 · 2018: 40
FWCI
5.22
Type
journal article
Language
en
Open access
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of General Medical Sciences (R01GM102519, R35GM122579)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD086730, R01HD086634)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
5' untranslated region, mRNA structure, translation initiation, cap-dependent translation, cap-independent translation, internal ribosome entry site, RNA structure probing, post-transcriptional regulation, RNA helicase, mRNA modification
MeSH terms
Internal Ribosome Entry Sites, Animals, Humans, Models, Biological, Models, Molecular, Peptide Chain Initiation, Translational, Ribosomes, RNA, Messenger, Protein Biosynthesis, 5' Untranslated Regions, RNA Helicases, Eukaryotic Initiation Factor-4F, Eukaryotic Initiation Factor-3, G-Quadruplexes, RNA Folding

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