Regulation of m(6)A Transcripts by the 3'→5' RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline.

N(6)-methyladenosine (m(6)A) is an essential internal RNA modification that is critical for gene expression control in most organisms. Proteins with a YTH domain recognize m(6)A 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 m(6)A reader that is essential for male and female fertility in mice. High-throughput mapping of the m(6)A transcriptome and expression analysis in the Yhtdc2 mutant testes reveal an upregulation of m(6)A-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 m(6)A-modified germline transcripts to maintain a gene expression program that is conducive for progression through meiosis.

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