Scientific article
Open access

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

Published inMolecular cell, vol. 82, no. 9, p. 1678-1690
Publication date2022-05-05
First online date2022-03-18

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.

  • DExH helicase
  • RBM46
  • RNA helicase
  • XRN1
  • YTH
  • YTHDC2
  • m(6)A
  • oogenesis
  • spermatogenesis
  • Animals
  • DNA-Binding Proteins / metabolism
  • Exoribonucleases / metabolism
  • Fertility / genetics
  • Mammals / metabolism
  • Meiosis
  • Mice
  • RNA / genetics
  • RNA Helicases / genetics
  • RNA Helicases / metabolism
  • Zebrafish / genetics
Research group
Citation (ISO format)
LI, Lingyun et al. The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m<sup>6</sup>A recognition. In: Molecular cell, 2022, vol. 82, n° 9, p. 1678–1690. doi: 10.1016/j.molcel.2022.02.034
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Article (Published version)
ISSN of the journal1097-2765

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