Regulation of m 6 A 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. Epub 2017 Oct 12.

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.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / genetics
  • Adenosine / metabolism
  • Animals
  • Ankyrin Repeat
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Exoribonucleases / genetics
  • Exoribonucleases / metabolism
  • Gene Expression Regulation / physiology*
  • Male
  • Meiosis / physiology*
  • Mice
  • Mice, Mutant Strains
  • Protein Domains
  • RNA Helicases / genetics
  • RNA Helicases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*

Substances

  • DNA-Binding Proteins
  • RNA, Messenger
  • N-methyladenosine
  • Exoribonucleases
  • Xrn1 protein, mouse
  • RNA Helicases
  • Adenosine