2. Academic Validation
  3. The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition

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.
Lingyun Li 1,  Kyrylo Krasnykov 1,  David Homolka 1,  Pascal Gos 1,  Mateusz Mendel 1,  Richard J Fish 2,  Radha Raman Pandey 3,  Ramesh S Pillai 4
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Science III, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.
  • 2 Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
  • 3 Department of Molecular Biology, Science III, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland. Electronic address: [email protected].
  • 4 Department of Molecular Biology, Science III, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland. Electronic address: [email protected].
PMID: 35305312 DOI: 10.1016/j.molcel.2022.02.034
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.

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