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

ABSTRACT: 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 ev

SUBMITTER: Baud A 

PROVIDER: S-EPMC12808120 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature