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DDX 3X and specific initiation factors modulate FMR 1 repeat‐associated non‐AUG‐initiated translation
Author(s) -
Linsalata Alexander E,
He Fang,
Malik Ahmed M,
Glineburg Mary Rebecca,
Green Katelyn M,
Natla Sam,
Flores Brittany N,
Krans Amy,
Archbold Hilary C,
Fedak Stephen J,
Barmada Sami J,
Todd Peter K
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201847498
Subject(s) - trinucleotide repeat expansion , ran , biology , eukaryotic initiation factor , eukaryotic translation , genetics , rna helicase a , fmr1 , translation (biology) , untranslated region , eukaryotic translation initiation factor 4 gamma , context (archaeology) , microbiology and biotechnology , start codon , eif4a1 , helicase , rna , messenger rna , gene , paleontology , allele , fragile x
A CGG trinucleotide repeat expansion in the 5′ UTR of FMR 1 causes the neurodegenerative disorder Fragile X‐associated tremor/ataxia syndrome ( FXTAS ). This repeat supports a non‐canonical mode of protein synthesis known as repeat‐associated, non‐ AUG ( RAN ) translation. The mechanism underlying RAN translation at CGG repeats remains unclear. To identify modifiers of RAN translation and potential therapeutic targets, we performed a candidate‐based screen of eukaryotic initiation factors and RNA helicases in cell‐based assays and a Drosophila melanogaster model of FXTAS . We identified multiple modifiers of toxicity and RAN translation from an expanded CGG repeat in the context of the FMR 1 5′ UTR . These include the DEAD ‐box RNA helicase belle / DDX 3X , the helicase accessory factors EIF 4B/4H , and the start codon selectivity factors EIF 1 and EIF 5 . Disrupting belle / DDX 3X selectively inhibited FMR 1 RAN translation in Drosophila in vivo and cultured human cells, and mitigated repeat‐induced toxicity in Drosophila and primary rodent neurons. These findings implicate RNA secondary structure and start codon fidelity as critical elements mediating FMR 1 RAN translation and identify potential targets for treating repeat‐associated neurodegeneration.