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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...

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Autores principales: Anderson, Rachel, Das, Michael, Chang, Yeonji, Farenhem, Kelsey, Jain, Ankur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
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.
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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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