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CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs
Expansions of CAG trinucleotide repeats cause several rare neurodegenerative diseases. The disease-causing repeats are translated in multiple reading frames, without an identifiable initiation codon. The molecular mechanism of this repeat-associated non-AUG (RAN) translation is not known. We find th...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614865/ https://www.ncbi.nlm.nih.gov/pubmed/37904984 http://dx.doi.org/10.1101/2023.10.16.562581 |
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author | Anderson, Rachel Das, Michael Chang, Yeonji Farenhem, Kelsey Jain, Ankur |
author_facet | Anderson, Rachel Das, Michael Chang, Yeonji Farenhem, Kelsey Jain, Ankur |
author_sort | Anderson, Rachel |
collection | PubMed |
description | Expansions of CAG trinucleotide repeats cause several rare neurodegenerative diseases. The disease-causing repeats are translated in multiple reading frames, without an identifiable initiation codon. The molecular mechanism of this repeat-associated non-AUG (RAN) translation is not known. We find that expanded CAG repeats create new splice acceptor sites. Splicing of proximal donors to the repeats produces unexpected repeat-containing transcripts. Upon splicing, depending on the sequences surrounding the donor, CAG repeats may become embedded in AUG-initiated open reading frames. Canonical AUG-initiated translation of these aberrant RNAs accounts for proteins that are attributed to RAN translation. Disruption of the relevant splice donors or the in-frame AUG initiation codons is sufficient to abrogate RAN translation. Our findings provide a molecular explanation for the abnormal translation products observed in CAG trinucleotide repeat expansion disorders and add to the repertoire of mechanisms by which repeat expansion mutations disrupt cellular functions. |
format | Online Article Text |
id | pubmed-10614865 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-106148652023-10-31 CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs Anderson, Rachel Das, Michael Chang, Yeonji Farenhem, Kelsey Jain, Ankur bioRxiv Article Expansions of CAG trinucleotide repeats cause several rare neurodegenerative diseases. The disease-causing repeats are translated in multiple reading frames, without an identifiable initiation codon. The molecular mechanism of this repeat-associated non-AUG (RAN) translation is not known. We find that expanded CAG repeats create new splice acceptor sites. Splicing of proximal donors to the repeats produces unexpected repeat-containing transcripts. Upon splicing, depending on the sequences surrounding the donor, CAG repeats may become embedded in AUG-initiated open reading frames. Canonical AUG-initiated translation of these aberrant RNAs accounts for proteins that are attributed to RAN translation. Disruption of the relevant splice donors or the in-frame AUG initiation codons is sufficient to abrogate RAN translation. Our findings provide a molecular explanation for the abnormal translation products observed in CAG trinucleotide repeat expansion disorders and add to the repertoire of mechanisms by which repeat expansion mutations disrupt cellular functions. Cold Spring Harbor Laboratory 2023-10-16 /pmc/articles/PMC10614865/ /pubmed/37904984 http://dx.doi.org/10.1101/2023.10.16.562581 Text en https://creativecommons.org/licenses/by-nc/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Anderson, Rachel Das, Michael Chang, Yeonji Farenhem, Kelsey Jain, Ankur CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs |
title | CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs |
title_full | CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs |
title_fullStr | CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs |
title_full_unstemmed | CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs |
title_short | CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs |
title_sort | cag repeat expansions create splicing acceptor sites and produce aberrant repeat-containing rnas |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614865/ https://www.ncbi.nlm.nih.gov/pubmed/37904984 http://dx.doi.org/10.1101/2023.10.16.562581 |
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