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<p>Mutant mRNA of the fragile X messenger ribonucleoprotein 1 gene (<i>FMR1</i>) containing expanded CGG repeats in its 5’UTR is a primary cause of fragile X premutation associated conditions. It serves as a template for the biosynthesis of the major open reading frame encoding canonical protein and the downstream open reading frame containing expanded CGG repeats encoding toxic FMRpolyG protein that comprise a long polyglycine stretch, produced via repeat-associated non-AUG initiated translation. Here, we show that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) binds directly to the 5’UTR of <i>FMR1</i> RNA, and the sequence in the vicinity of near-cognate start codons of non-AUG translation is pivotal for IGF2BP3 binding. Upon IGF2BP3’s knockdown, FMRpolyG biosynthesis and cell toxicity evoked by FMRpolyG, significantly decreased in cells expressing mutant <i>FMR1</i> with expanded CGG repeats. Disruption of IGF2BP ortholog in novel fragile X premutation associated conditions <i>C. elegans</i> model rescues the disease phenotype induced by expression of a human <i>FMR1</i> RNA fragment containing expanded CGG repeats. Our results suggest that IGF2BP3 positively regulates the noncanonical translation of expanded CGG repeats and may be a promising target for clinical applications.</p>

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IGF2BPs directly regulate the noncanonical translation of toxic proteins from mutant FMR1 mRNA containing expanded CGG repeats

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Anna Baud,
  • Damini Saha,
  • Tomasz Skrzypczak,
  • Izabela Broniarek,
  • Daria Niewiadomska,
  • Wojciech J. Szlachcic,
  • Malgorzata Borowiak,
  • Rajani Kanth Gudipati,
  • Krzysztof Sobczak

摘要

Mutant mRNA of the fragile X messenger ribonucleoprotein 1 gene (FMR1) containing expanded CGG repeats in its 5’UTR is a primary cause of fragile X premutation associated conditions. It serves as a template for the biosynthesis of the major open reading frame encoding canonical protein and the downstream open reading frame containing expanded CGG repeats encoding toxic FMRpolyG protein that comprise a long polyglycine stretch, produced via repeat-associated non-AUG initiated translation. Here, we show that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) binds directly to the 5’UTR of FMR1 RNA, and the sequence in the vicinity of near-cognate start codons of non-AUG translation is pivotal for IGF2BP3 binding. Upon IGF2BP3’s knockdown, FMRpolyG biosynthesis and cell toxicity evoked by FMRpolyG, significantly decreased in cells expressing mutant FMR1 with expanded CGG repeats. Disruption of IGF2BP ortholog in novel fragile X premutation associated conditions C. elegans model rescues the disease phenotype induced by expression of a human FMR1 RNA fragment containing expanded CGG repeats. Our results suggest that IGF2BP3 positively regulates the noncanonical translation of expanded CGG repeats and may be a promising target for clinical applications.