Related Experiment Video
Updated: Sep 9, 2025
10:49
Measuring RAN Peptide Toxicity in C. elegans
Published on: April 30, 2020
6.7K
m6A modulates RAN translation from CAG repeat expansion RNA
Yuxiang Sun1,2, Zhouxian Li1, Hui Dai1
1Department of Chemistry, University of California Riverside, Riverside, CA 92521-0403.
Aggregate (Hoboken, N.J.)
|August 29, 2025
Summary
Methylation (m6A) promotes repeat-associated non-AUG (RAN) translation from expanded CAG repeats in spinocerebellar ataxia type 3 (SCA3). METTL3 facilitates this process, while FTO removes the methylation mark, impacting RAN translation products.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Nucleotide repeat expansions are implicated in neurodegenerative diseases.
- Repeat-associated non-AUG (RAN) translation of expanded repeat RNA is a known but poorly understood mechanism.
Purpose of the Study:
- To elucidate the mechanisms regulating RAN translation from expanded CAG repeat RNA.
- To investigate the role of RNA methylation, specifically m6A, in this process.
Main Methods:
- Investigated the role of METTL3 (m6A writer) and FTO (m6A eraser) in RAN translation.
- Utilized genetic depletion, pharmacological inhibition, and ectopic expression of METTL3.
- Analyzed RAN translation products from expanded CAG repeat RNA of the human ATXN3 gene.
Main Results:
- m6A modification, installed by METTL3 and removed by FTO, promotes RAN translation in all three reading frames.
- METTL3 depletion/inhibition reduced RAN products; restoration occurred with wild-type METTL3 but not inactive mutant.
- FTO ablation increased RAN products.
- Poly(serine) RAN product formed gel-like aggregates.
Conclusions:
- m6A plays a critical role in modulating RAN translation from expanded CAG repeat RNA in SCA3.
- Identified novel biophysical properties of the poly(serine) RAN translation product.
Related Concept Videos
02:28Leaky Scanning
5.2K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.2K
01:29Translational Regulation
91
Translational regulation in prokaryotes ensures efficient protein synthesis by controlling ribosome access to mRNA. This regulation is mediated by secondary RNA structures, including translational riboswitches, RNA thermometers, and small RNAs (sRNAs), which respond to intracellular and environmental signals to modulate gene expression.Translational RiboswitchesRiboswitches in the leader region of mRNAs can regulate translation by altering the accessibility of the Shine-Dalgarno (SD) sequence,...
91
01:23Regulation of Expression at Multiple Steps
994
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
994
01:53RNA Stability
33.9K
Intact DNA strands can be found in fossils, while scientists sometimes struggle to keep RNA intact under laboratory conditions. The structural variations between RNA and DNA underlie the differences in their stability and longevity. Because DNA is double-stranded, it is inherently more stable. The single-stranded structure of RNA is less stable but also more flexible and can form weak internal bonds. Additionally, most RNAs in the cell are relatively short, while DNA can be up to 250 million...
33.9K
02:23RNA Editing
9.2K
RNA editing is a post-transcriptional modification where a precursor mRNA (pre-mRNA) nucleotide sequence is changed by base insertion, deletion, or modification. The extent of RNA editing varies from a few hundred bases, in mitochondrial DNA of trypanosomes, to a just single base, in nuclear genes of mammals. Even a single base change in the pre-mRNA can convert a codon for one amino acid into the codon for another amino acid or a stop codon. This type of re-coding can significantly affect the...
9.2K
02:24Regulation of Expression Occurs at Multiple Steps
23.2K
Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
23.2K