2. Academic Validation
  3. Regulation of m6A Transcripts by the 3'→5' RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline

Regulation of m6A Transcripts by the 3'→5' RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline

  • Mol Cell. 2017 Oct 19;68(2):374-387.e12. doi: 10.1016/j.molcel.2017.09.021.
Magdalena Natalia Wojtas 1,  Radha Raman Pandey 1,  Mateusz Mendel 2,  David Homolka 1,  Ravi Sachidanandam 3,  Ramesh S Pillai 4
Affiliations

Affiliations

  • 1 Department of Molecular Biology, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland; European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042 Grenoble, France.
  • 2 Department of Molecular Biology, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.
  • 3 Department of Oncological Sciences, Icahn School of Medicine at Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
  • 4 Department of Molecular Biology, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland; European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042 Grenoble, France. Electronic address: ramesh.pillai@unige.ch.
PMID: 29033321 DOI: 10.1016/j.molcel.2017.09.021
Abstract

N6-methyladenosine (m6A) is an essential internal RNA modification that is critical for gene expression control in most organisms. Proteins with a YTH domain recognize m6A marks and are mediators of molecular functions like RNA splicing, mRNA decay, and translation control. Here we demonstrate that YTH domain-containing 2 (YTHDC2) is an m6A reader that is essential for male and female fertility in mice. High-throughput mapping of the m6A transcriptome and expression analysis in the Yhtdc2 mutant testes reveal an upregulation of m6A-enriched transcripts. Our biochemical studies indicate that YTHDC2 is an RNA-induced ATPase with a 3'→5' RNA helicase activity. Furthermore, YTHDC2 recruits the 5'→3' exoribonuclease XRN1 via Ankyrin repeats that are inserted in between the RecA modules of the RNA helicase domain. Our studies reveal a role for YTHDC2 in modulating the levels of m6A-modified germline transcripts to maintain a gene expression program that is conducive for progression through meiosis.

Keywords

ATPase; CAHL; DExH; MEIOC; RNA helicase; XRN1; YTH; YTHDC2; m(6)A; spermatogenesis.

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