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Mol Cell. 2016 Apr 21;62(2):314-322. doi: 10.1016/j.molcel.2016.02.034. Epub 2016 Mar 31.

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

Author information

1
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
2
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
3
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Veterans Affairs Medical Center, Ann Arbor, MI 48105, USA.
4
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
5
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
6
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Veterans Affairs Medical Center, Ann Arbor, MI 48105, USA; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: petertod@umich.edu.

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 m(7)G 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.

PMID:
27041225
PMCID:
PMC4854189
DOI:
10.1016/j.molcel.2016.02.034
[Indexed for MEDLINE]
Free PMC Article

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