The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition
Lingyun Li, Kyrylo Krasnykov, David Homolka, Pascal Gos, Mateusz Mendel, Richard J. Fish, Radha Raman Pandey, Ramesh S. Pillai
Abstract
A-binder in vitro, the YTH point mutant mice are fertile. Significantly, the loss of its 3'→5' RNA helicase activity causes mouse infertility, with the catalytic-dead mutation being dominant negative. Biochemical studies reveal that the weak helicase activity of YTHDC2 is enhanced by its interaction with the 5'→3' exoribonuclease XRN1. Single-cell transcriptomics indicate that Ythdc2 mutant mitotic germ cells transition into meiosis but accumulate a transcriptome with mixed mitotic/meiotic identity that fail to progress further into meiosis. Finally, our demonstration that ythdc2 mutant zebrafish are infertile highlights its conserved role in animal germ cell development.