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CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning
Mechanism of Initiation to Produce Toxic Proteins
#MMPMID27041225
Kearse MG
; Green KM
; Krans A
; Rodriguez CM
; Linsalata AE
; Goldstrohm AC
; Todd PK
Mol Cell
2016[Apr]; 62
(2
): 314-322
PMID27041225
show ga
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.
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