m6A modification of U6 snRNA modulates usage of two major classes of pre-mRNA 5' splice site

Matthew T. Parker, Beth K. Soanes, Jelena Kusakina, Antoine Larrieu, Katarzyna Knop, Nisha Joy, Friedrich Breidenbach, Anna V. Sherwood, Geoffrey J. Barton, Sebastian M. Fica, Brendan H. Davies (Lead / Corresponding author), Gordon Grant Simpson (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
63 Downloads (Pure)

Abstract

Alternative splicing of messenger RNAs is associated with the evolution of developmentally complex eukaryotes. Splicing is mediated by the spliceosome, and docking of the pre-mRNA 5' splice site into the spliceosome active site depends upon pairing with the conserved ACAGA sequence of U6 snRNA. In some species, including humans, the central adenosine of the ACAGA box is modified by N6 methylation, but the role of this m6A modification is poorly understood. Here, we show that m6A modified U6 snRNA determines the accuracy and efficiency of splicing. We reveal that the conserved methyltransferase, FIONA1, is required for Arabidopsis U6 snRNA m6A modification. Arabidopsis fio1 mutants show disrupted patterns of splicing that can be explained by the sequence composition of 5' splice sites and cooperative roles for U5 and U6 snRNA in splice site selection. U6 snRNA m6A influences 3' splice site usage. We generalise these findings to reveal two major classes of 5' splice site in diverse eukaryotes, which display anti-correlated interaction potential with U5 snRNA loop 1 and the U6 snRNA ACAGA box. We conclude that U6 snRNA m6A modification contributes to the selection of degenerate 5' splice sites crucial to alternative splicing.

Original languageEnglish
Article numbere78808
Number of pages34
JournaleLife
Volume11
Early online date21 Nov 2022
DOIs
Publication statusPublished - 30 Dec 2022

Keywords

  • A. thaliana
  • C. elegans
  • D. melanogaster
  • ambient temperature
  • chromosomes
  • epitranscriptome
  • flowering time
  • gene expression
  • genetics
  • genomics
  • human
  • m6A
  • splicing
  • zebrafish

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology

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