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bioRxiv · 10.1101/2023.10.16.562581

CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs

Anderson, R. J.·Das, M. R.·Chang, Y.·Farenhem, K.·Jain, A.
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Abstract

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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Anderson, R. J., Das, M. R., Chang, Y., Farenhem, K., Jain, A.. 2023-10-16. CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs. https://doi.org/10.1101/2023.10.16.562581

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