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FMRP drives mRNP targets into translationally silenced complexes

  1. Author:
    Kurosaki, Tatsuaki
    Cho, Hana
    Abshire, Elizabeth T
    Pröschel, Christoph
    Mitsutomi, Shuhei
    Sato, Hanae
    Simko, Eric A J
    Fraser, Christopher S
    Sakano, Hitomi
    Maquat, Lynne E
  2. Author Address

    Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA; Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA; Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine & Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA., Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA; Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA., Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA; Department of Biomedical Genetics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA; Stem Cell and Regenerative Medicine Institute, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA., National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA., Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, CA 95616, USA., Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA; Department of Otolaryngology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA., Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA; Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA. Electronic address: lynne_maquat@urmc.rochester.edu.,
    1. Year: 2025
    2. Date: Jul 08
    3. Epub Date: 2025 07 08
  1. Journal: Molecular Cell
  2. Type of Article: Article
  1. Abstract:

    Fragile X syndrome (FXS) results from a deficiency of the ubiquitously expressed RNA-binding protein fragile X protein (FMRP). While FMRP-mediated translational repression has been attributed primarily to ribosome stalling, using immunoprecipitations and polysome profiling of non-polar- and polar-cell lysates and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses, we show that mammalian FMRP largely represses translation initiation by associating with granule constituents to preclude 40S ribosomal subunit binding. We demonstrate that FMRP associates with its target mRNAs by binding directly to eukaryotic translation initiation factor 4E (eIF4E) at the 5' cap in competition with eIF4G1 and that ataxin-2-like promotes FMRP binding to the transcribed body. The KH1 + KH2 domains of FMRP are critical for the co-immunoprecipitation of eIF4E, mRNA targets, ataxin-2-like, and PABPC1. Our findings supplement FMRP-mediated ribosome-stalling data, suggesting that FMRP largely mediates the sequestration of its mRNA targets from translation initiation and degradation in a network of FMRP molecules that simultaneously associate with cap-bound eIF4E, GC-rich mRNA regions, and poly(A)-bound PABPC1. Copyright © 2025 Elsevier Inc. All rights reserved.

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External Sources

  1. DOI: 10.1016/j.molcel.2025.06.012
  2. PMID: 40645180
  3. PMCID: PMC12258928
  4. PII : S1097-2765(25)00512-X

Library Notes

  1. Fiscal Year: FY2024-2025
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