CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins

Michael G. Kearse, Katelyn M. Green, Amy Krans, Caitlin M. Rodriguez, Alexander E. Linsalata, Aaron Goldstrohm, Peter K. Todd

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Repeat-associated non-AUG (RAN) translation produces toxic polypeptides from nucleotide repeat expansions in the absence of an AUG start codon and contributes to neurodegenerative disorders such as ALS and fragile X-associated tremor/ataxia syndrome. How RAN translation occurs is unknown. Here we define the critical sequence and initiation factors that mediate CGG repeat RAN translation in the 5' leader of fragile X mRNA, FMR1. Our results reveal that CGG RAN translation is 30%-40% as efficient as AUG-initiated translation, is m7G cap and eIF4E dependent, requires the eIF4A helicase, and is strongly influenced by repeat length. However, it displays a dichotomous requirement for initiation site selection between reading frames, with initiation in the +1 frame, but not the +2 frame, occurring at near-cognate start codons upstream of the repeat. These data support a model in which RAN translation at CGG repeats uses cap-dependent ribosomal scanning, yet bypasses normal requirements for start codon selection. AUG-independent translation of expanded nucleotide repeats produces toxic neuronal proteins. Kearse et al. show that RAN translation of CGG repeats initiates similarly to canonical translation, requiring an m7G cap and 40S ribosomal scanning. However, initiation codon selection differs across repeat reading frames and with repeat expansion.

Original languageEnglish (US)
Pages (from-to)314-322
Number of pages9
JournalMolecular Cell
Volume62
Issue number2
DOIs
StatePublished - Apr 21 2016

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Initiator Codon
Poisons
Reading Frames
Proteins
Nucleotides
Peptide Initiation Factors
Neurodegenerative Diseases
Messenger RNA
Peptides

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CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins. / Kearse, Michael G.; Green, Katelyn M.; Krans, Amy; Rodriguez, Caitlin M.; Linsalata, Alexander E.; Goldstrohm, Aaron; Todd, Peter K.

In: Molecular Cell, Vol. 62, No. 2, 21.04.2016, p. 314-322.

Research output: Contribution to journalArticle

Kearse, Michael G. ; Green, Katelyn M. ; Krans, Amy ; Rodriguez, Caitlin M. ; Linsalata, Alexander E. ; Goldstrohm, Aaron ; Todd, Peter K. / CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins. In: Molecular Cell. 2016 ; Vol. 62, No. 2. pp. 314-322.
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