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Updated: Jul 4, 2025
08:53
A Reporter Based Cellular Assay for Monitoring Splicing Efficiency
Published on: September 15, 2021
2.8K
CAG repeat expansions create splicing acceptor sites and produce aberrant repeat-containing RNAs
Rachel Anderson1, Michael R Das1, Yeonji Chang2
1Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA.
Molecular Cell
|January 31, 2024
Summary
Expanded CAG repeats in neurodegenerative diseases create new splice sites, leading to abnormal protein production via standard translation. This explains repeat-associated non-AUG (RAN) translation mechanisms.
Area of Science:
- Genetics
- Molecular Biology
- Neuroscience
Background:
- Expansions of CAG trinucleotide repeats are linked to rare neurodegenerative diseases.
- The mechanism behind repeat-associated non-AUG (RAN) translation remains unknown.
Purpose of the Study:
- To elucidate the molecular mechanism of RAN translation in CAG repeat expansion disorders.
Main Methods:
- Investigated the role of splicing in the formation of repeat-containing transcripts.
- Analyzed the initiation of translation from these aberrant RNAs.
- Assessed the impact of disrupting splice donors and initiation codons on RAN translation.
Main Results:
- Expanded CAG repeats create novel splice acceptor sites.
- Splicing generates repeat-containing transcripts that can be embedded in AUG-initiated open reading frames.
- Canonical translation of these aberrant RNAs can produce proteins previously attributed to RAN translation.
- Disrupting splice donors or AUG initiation codons prevents RAN translation.
Conclusions:
- CAG repeat expansions can lead to abnormal protein synthesis through a splicing-dependent mechanism.
- This mechanism provides a molecular explanation for RAN translation in repeat expansion disorders.
- These findings expand the understanding of how repeat expansions disrupt cellular function.
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