Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing
A new study published in Cell shows that the N6-methyladenosine (m6A) RNA modification inhibits splicing by blocking U2AF35 splicing factor binding to the 3’ splice acceptor sites. In the nematode C. elegans, this mechanism is used to regulate SAM synthetase (the enzyme producing the methyl donor for m6A) mRNA levels in response to diet. When worms are fed a rich diet, the SAM mRNA is methylated, gene splicing is blocked and the availability of methyl donors decreases. When nutrients are limiting, methylation levels decrease and splicing is not blocked, thus increasing synthesis of methyl donors.
The illustration represents the inhibitory effect of m6A on splice factor binding. When the 3' splice site is unmethylated, the lamp glows bright thus attracting moths, here representing splice factors. When m6A is present, the dimly lit lamp isn't "seen" anymore by the moths.
Mendel M, Delaney K, Pandey RR, Chen KM, Wenda JM, Vågbø CB, Steiner FA, Homolka D, Pillai RS. Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicing. Cell. 2021 Apr 27:S0092-8674(21)00435-9. doi: 10.1016/j.cell.2021.03.062. Epub ahead of print. PMID: 33930289.