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Cited by 822DNA and Nucleic Acid ChemistryRNA and protein synthesis mechanismsRNA Research and Splicing

An RNA G-quadruplex in the 5′ UTR of the NRAS proto-oncogene modulates translation

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Kumari, Sunita, Bugaut, Anthony, Huppert, Julian L, Balasubramanian, Shankar·2007·Nature Chemical Biology
DOI 10.1038/nchembio864PMC PMC2206252
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Abstract

Guanine-rich nucleic acid sequences can adopt noncanonical four-stranded secondary structures called guanine (G)-quadruplexes. Bioinformatics analysis suggests that G-quadruplex motifs are prevalent in genomes, which raises the need to elucidate their function. There is now evidence for the existence of DNA G-quadruplexes at telomeres with associated biological function. A recent hypothesis supports the notion that gene promoter elements contain DNA G-quadruplex motifs that control gene expression at the transcriptional level. We discovered a highly conserved, thermodynamically stable RNA G-quadruplex in the 5' untranslated region (UTR) of the gene transcript of the human NRAS proto-oncogene. Using a cell-free translation system coupled to a reporter gene assay, we have demonstrated that this NRAS RNA G-quadruplex modulates translation. This is the first example of translational repression by an RNA G-quadruplex. Bioinformatics analysis has revealed 2,922 other 5' UTR RNA G-quadruplex elements in the human genome. We propose that RNA G-quadruplexes in the 5' UTR modulate gene expression at the translational level.

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  • The translational repression function of G-quadruplex is reinforced by the presence of FMRP.

    “This function is reinforced by the presence of FMRP (Kumari et al., 2007; Melko and Bardoni, 2010).”

    From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Kumari et al., 2007

    The passage indexed under Abstract (page unavailable) reports that the NRAS RNA G-quadruplex suppresses translation. It does not mention FMRP or show that FMRP reinforces this effect; searches for FMRP and protein binding found no supporting passage. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • eIF4A can bind to mRNA immediately before translation initiation and unwind such mRNA structures, thereby clearing the path for scanning.

    “initiation factor 4A (eIF4A) can bind to mRNA immediately before translation initiation and unwind such mRNA structures, thereby clearing the path for scanning [9].”

    From Effects of Combinations of Untranslated-Region Sequences on Translation of mRNA (2023) · cites this paper as [9]

    The paper’s Abstract reports that an NRAS 5′-UTR G-quadruplex inhibits translation, but says its inhibitory mechanism remains to be elucidated. Searches for eIF4A, helicase activity, and scanning found no passage stating that eIF4A binds and unwinds mRNA structures before initiation. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 19

  1. [1]Neidle S Balasubramanian S Quadruplex Nucleic Acids 2006 Cambridge RSC Biomolecular Sciences
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  3. [3]Paeschke K Simonsson T Postberg J Rhodes D Lipps HJ Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo Nat. Struct. Mol. Biol 2005 12 847 854 16142245
  4. [4]Siddiqui-Jain A Grand CL Bearss DJ Hurley LH Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription Proc. Natl. Acad. Sci. USA 2002 99 11593 11598 12195017 PMC129314
  5. [5]Saccà B Lacroix L Mergny J-L The effect of chemical modifications on the thermal stability of different G-quadruplex-forming oligonucleotides Nucleic Acids Res 2005 33 1182 1192 15731338 PMC549566
  6. [6]Willis AE Translational control of growth factor and proto-oncogene expression Int. J. Biochem. Cell Biol 1999 31 73 86 10216945
  7. [7]Downward J Targeting Ras signalling pathways in cancer therapy Nat. Rev. Cancer 2003 3 11 22 12509763
  8. [8]Barbacid M Ras genes Annu. Rev. Biochem 1987 56 779 827 3304147
  9. [9]Eskandarpour M Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells Int. J. Cancer 2005 115 65 73 15688405
  10. [10]Hall A Brown R Human N-ras: cDNA cloning and gene structure Nucleic Acids Res 1985 13 5255 5268 2991860 PMC321863
  11. [11]Balagurumoorthy P Brahmachari SK Mohanty D Bansal M Sasisekharan V Hairpin and parallel quartet structure for telomeric sequences Nucleic Acids Res 1992 20 4061 4067 1508691 PMC334088
  12. [12]Tang C-F Shafer RH Engineering the quadruplex fold: nucleoside conformation determines both folding topology and molecularity in guanine quadruplexes J. Am. Chem. Soc 2006 128 5966 5973 16637665 PMC2597528
  13. [13]Mergny J-L Phan A-T Lacroix L Following G-quartet formation by UV-spectroscopy FEBS Lett 1998 435 74 78 9755862
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  15. [15]DiLella AG Utility of firefly luciferase as a reporter gene for promoter activity in transgenic mice Nucleic Acids Res 1988 16 4159 3375079 PMC336585
  16. [16]Kozak M Structural features in eukaryotic mRNAs that modulate the initiation of translation J. Biol. Chem 1991 266 19867 19870 1939050
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  19. [19]Mergny JL Lacroix L Analysis of thermal melting curves Oligonucleotides 2003 13 515 537 15025917

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Authors
Kumari, S., Bugaut, A., Huppert, J. L., & Balasubramanian, S.
Affiliations
  • University of Cambridge (GB)
  • Wellcome Sanger Institute (GB)
Corresponding author
Balasubramanian, Shankar
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2007-02-25
Volume
3
Issue
4
Pages
218-221
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/nchembio864
PMC
PMC2206252
OpenAlex
W2032698727
Cited by
822
References
0
Citations by year
2026: 35 · 2025: 39 · 2024: 55 · 2023: 45 · 2022: 40 · 2021: 49 · 2020: 59 · 2019: 47 · 2018: 47 · 2017: 34 · 2016: 42 · 2015: 36 · 2014: 43 · 2013: 46 · 2012: 45
FWCI
14.72
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Cancer Research UK (A4081)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • 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
Keywords
RNA G-quadruplex, NRAS, 5' untranslated region, protein synthesis inhibition, translational regulation, gene expression regulation, in vitro translation, human genome
MeSH terms
Proto-Oncogene Mas, Animals, Base Sequence, DNA, Guanine, Humans, Molecular Sequence Data, Plasmids, Protein Biosynthesis, Gene Expression, Proto-Oncogene Proteins p21(ras), 5' Untranslated Regions, G-Quadruplexes

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