U6 snRNA m6A modification is required for accurate and efficient splicing of C. elegans and human pre-mRNAs.
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Peer-reviewed
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Abstract
pre-mRNA splicing is a critical feature of eukaryotic gene expression. Both cis- and trans-splicing rely on accurately recognising splice site sequences by spliceosomal U snRNAs and associated proteins. Spliceosomal snRNAs carry multiple RNA modifications with the potential to affect different stages of pre-mRNA splicing. Here, we show that the conserved U6 snRNA m6A methyltransferase METT-10 is required for accurate and efficient cis- and trans-splicing of C. elegans pre-mRNAs. The absence of METT-10 in C. elegans and METTL16 in humans primarily leads to alternative splicing at 5' splice sites with an adenosine at +4 position. In addition, METT-10 is required for splicing of weak 3' cis- and trans-splice sites. We identified a significant overlap between METT-10 and the conserved splicing factor SNRNP27K in regulating 5' splice sites with +4A. Finally, we show that editing endogenous 5' splice site +4A positions to +4U restores splicing to wild-type positions in a mett-10 mutant background, supporting a direct role for U6 snRNA m6A modification in 5' splice site recognition. We conclude that the U6 snRNA m6A modification is important for accurate and efficient pre-mRNA splicing.
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Funder: Pew Scholar, and Southwestern Medical Foundation Scholar in Biomedical Research
Funder: UKRI bloc funds
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1362-4962
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UK Research and Innovation Biotechnology and Biological Sciences Research Council Norwich Research Park Biosciences Doctoral Training Partnership (BB/T008717/1)
UK Research and Innovation Biotechnology and Biological Sciences Research Council (BB/CCG1720/1, BS/E/T/000PR9818, BB/W007673/1, BB/V010662/1)
UK Research and Innovation Medical Research Council (MR/P026028/1)
US National Institutes of Health (R01GM122960, R01CA258589)
Welch Foundation (I-2115-20220331)