The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif
Open accessAbstract
Fragile X syndrome is caused by the absence of protein FMRP, the function of which is still poorly understood. Previous studies have suggested that FMRP may be involved in various aspects of mRNA metabolism, including transport, stability and/or translatability. FMRP was shown to interact with a subset of brain mRNAs as well as with its own mRNA; however, no specific RNA-binding site could be identified precisely. Here, we report the identification and characterization of a specific and high affinity binding site for FMRP in the RGG-coding region of its own mRNA. This site contains a purine quartet motif that is essential for FMRP binding and can be substituted by a heterologous quartet-forming motif. The specific binding of FMRP to its target site was confirmed further in a reticulocyte lysate through its ability to repress translation of a reporter gene harboring the RNA target site in the 5'-untranslated region. Our data address interesting questions concerning the role of FMRP in the post-transcriptional control of its own gene and possibly other target genes.
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The G-quadruplex/FMRP complex mediates the repression activity of FMRP in translational regulation.
“Moreover, the G-quadruplex/FMRP complex mediates the repression activity of FMRP in translational regulation (Schaeffer et al., 2001; Brown et al., 2001; Castets et al., 2005; Melko and Bardoni, 2010; Suhl et al., 2015).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Schaeffer et al., 2001
In “FMRP-FBS interaction occurring in chimeric mRNAs is capable of inhibiting translation in vitro” (page unavailable), the paper reports that FMRP binding to the purine-quartet-containing site represses translation of a reporter with that site in its 5′ UTR. The claim generalizes this experimental result to FMRP’s translational repression activity; “Implications for FMRP functions” says the mechanism for regulation of FMRP’s own mRNA remains to be demonstrated. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn Fmr1-null cells, the expression level of luciferase under the control of a G-quadruplex structure is increased because of the absence of the repression activity of FMRP.
“As expected (and as shown in Schaeffer et al., 2001), in Fmr1-null cells, the expression level of luciferase is increased because of the absence of the repression activity of FMRP (Fig. 4A).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Schaeffer et al., 2001
In the section “FMRP-FBS interaction occurring in chimeric mRNAs is capable of inhibiting translation in vitro” (page unavailable), the paper reports that adding FMRP suppresses translation of a luciferase reporter containing the purine-quartet binding site. That supports FMRP’s repressive activity, but the experiment used rabbit reticulocyte lysate, not Fmr1-null cells; the cited paper does not establish increased luciferase expression in those cells. (LLM, conf=0.88)
Experimental — accuracy not yet measuredG-quadruplex mRNA is a structure bound by FMRP and is harbored by some of its critical targets, including MAP1B, PP2AC, FMR1, SHANKL and SEMA3F.
“G-quadruplex mRNA is a structure bound by FMRP harbored by some of its critical targets (MAP1B, PP2AC, FMR1, SHANKL, SEMA3F) (Brown et al., 2001; Castets et al., 2005; Schaeffer et al., 2001; Zhang et al., 2014; Menon and Mihailescu, 2007).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Schaeffer et al., 2001
The Introduction and ‘A specific RNA motif for FMRP binding’ (page not provided) report that FMRP binds a purine-quartet motif in its own FMR1 mRNA, supporting the FMR1 example and the general structural claim. The paper does not establish the listed motifs or FMRP binding for MAP1B, PP2AC, SHANKL, or SEMA3F. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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“The level of luciferase encoded by an mRNA harboring a G-quadruplex in its 5 ′ UTR in the presence of FMRP is not modified upon CYFIP1 depletion (Fig.”
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- Authors
- Schaeffer, C., Bardoni, B., Mandel, J., Ehresmann, B., Ehresmann, C., & Moine, H.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Moine, Hervé
- Venue
- The EMBO Journal
- Published
- 2001-09-03
- Volume
- 20
- Issue
- 17
- Pages
- 4803-4813
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC125594
- OpenAlex
- W1997836836
- Cited by
- 471
- References
- 4
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 17 · 2021: 16 · 2020: 16 · 2019: 18 · 2018: 15 · 2017: 14 · 2016: 11 · 2015: 15 · 2014: 23 · 2013: 21 · 2012: 20
- FWCI
- 17.88
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- FRAXA Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- FMRP, fragile X syndrome, RNA-binding proteins, RGG domain, mRNA binding sites, post-transcriptional regulation, protein synthesis inhibition, 5' untranslated region, mRNA stability, mRNA transport
- MeSH terms
- Animals, Base Sequence, Binding Sites, Chickens, Fragile X Syndrome, Gene Expression Regulation, Humans, Kinetics, Intellectual Disability, Molecular Sequence Data, Nerve Tissue Proteins, Recombinant Fusion Proteins, RNA, Messenger, Sequence Homology, Nucleic Acid, Protein Biosynthesis, Vertebrates, Xenopus laevis, Sequence Alignment, RNA-Binding Proteins, Xenopus Proteins, Mice, Rats, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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