An Expanded CAG Repeat in Huntingtin Causes+1 Frameshifting
- 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.
Author details: | Paul Saffert, Frauke AdamlaGND, Rico Schieweck, John F. Atkins, Zoya Ignatova |
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DOI: | https://doi.org/10.1074/jbc.M116.744326 |
ISSN: | 0021-9258 |
ISSN: | 1083-351X |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/27382061 |
Title of parent work (English): | The journal of biological chemistry |
Publisher: | American Society for Biochemistry and Molecular Biology |
Place of publishing: | Bethesda |
Publication type: | Article |
Language: | English |
Year of first publication: | 2016 |
Publication year: | 2016 |
Release date: | 2020/03/22 |
Tag: | Huntington disease; aggregation; frameshifting; seeding; translation; translation regulation; trinucleotide repeat disease |
Volume: | 291 |
Number of pages: | 9 |
First page: | 18505 |
Last Page: | 18513 |
Funding institution: | Deutsche Forschungsgemeinschaft [FOR 1805, SFB 740]; Science Foundation Ireland |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
Peer review: | Referiert |