The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition

Mol Cell. 2022 May 5;82(9):1678-1690.e12. doi: 10.1016/j.molcel.2022.02.034. Epub 2022 Mar 18.

Abstract

The functional consequence of N6-methyladenosine (m6A) RNA modification is mediated by "reader" proteins of the YTH family. YTH domain-containing 2 (YTHDC2) is essential for mammalian fertility, but its molecular function is poorly understood. Here, we identify U-rich motifs as binding sites of YTHDC2 on 3' UTRs of mouse testicular RNA targets. Although its YTH domain is an m6A-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.

Keywords: DExH helicase; MEIOC; RBM46; RNA helicase; XRN1; YTH; YTHDC2; m(6)A; oogenesis; spermatogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / metabolism*
  • Exoribonucleases / metabolism*
  • Fertility / genetics
  • Mammals / metabolism
  • Meiosis
  • Mice
  • RNA / genetics
  • RNA Helicases* / genetics
  • RNA Helicases* / metabolism
  • Zebrafish* / genetics

Substances

  • DNA-Binding Proteins
  • RNA
  • Exoribonucleases
  • Xrn1 protein, mouse
  • RNA Helicases
  • Ythdc2 protein, mouse