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An expanded CAG repeat in Huntingtin Causes +1 frameshifting
Saffert, Paul; Adamla, Frauke; Schieweck, Rico; Atkins, John F.; Ignatova, Zoya
Maintenance of triplet decoding is crucial for the expression of functional protein because deviations either into the −1 or +1 reading frames are often non-functional. We report here that expression of huntingtin (Htt) exon 1 with expanded CAG repeats, implicated in Huntington pathology, undergoes a sporadic +1 frameshift to generate from the CAG repeat a trans-frame AGC repeat-encoded product. This +1 recoding is exclusively detected in pathological Htt variants, i.e. those with expanded repeats with more than 35 consecutive CAG codons. An atypical +1 shift site, UUC C at the 5′ end of CAG repeats, which has some resemblance to the influenza A virus shift site, triggers the +1 frameshifting and is enhanced by the increased propensity of the expanded CAG repeats to form a stem-loop structure. The +1 trans-frame-encoded product can directly influence the aggregation of the parental Htt exon 1.
Keyword(s): Aggregation; Huntington disease; Translation; Translation regulation; Trinucleotide repeat disease; Frameshifting; Seeding
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: University College Cork
Funder(s): Science Foundation Ireland
Citation(s): Saffert, P., Adamla, F., Schieweck, R., Atkins, J. F. and Ignatova, Z. (2016) 'An Expanded CAG Repeat in Huntingtin Causes +1 Frameshifting', Journal of Biological Chemistry, 291(35), pp. 18505-18513. doi: 10.1074/jbc.M116.744326
Publisher(s): American Society for Biochemistry and Molecular Biology
File Format(s): application/pdf
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First Indexed: 2018-03-29 06:30:12 Last Updated: 2018-03-29 06:30:12