m6A-mediated nonhomologous end joining (NHEJ) pathway regulates senescence in Brachionus plicatilis (Rotifera).

Epigenetic modifications play an important role in the regulation of senescence. N6-methyladenosine (m6A) is the most abundant modification of mRNA. However, the impact of m6A on senescence remains largely unknown at the animal individual level. Standard model organisms Caenorhabditis elegans and Drosophila melanogaster lack many gene homologs of vertebrate m6A system that are present in other invertebrates. In this study, we employed a small aquatic invertebrate Brachionus plicatilis which has been used in aging studies for nearly 100 years to study how m6A affects aging. Phylogenetic analysis confirmed that rotifers' m6A pathway has a conserved methyltransferase complex but no demethylases and the m6A reading system was more akin to that of vertebrates than that of D. melanogaster. m6A methyltransferases are highly expressed during development but reduces dramatically during aging. Knockdown of METTL3 results in decreased fecundity and premature senescence of rotifers. Furthermore, RT-qPCR analysis indicates a role for m6A in the nonhomologous end joining (NHEJ) pathway of DNA double-strand breaks (DSBs) repair. Altogether, our work reveals a senescence regulatory model for the rotifer METTL3-m6A-NHEJ pathway.