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

• DOI: 10.1016/j.molcel.2017.09.021
• Publication Date: 2017-10-13T15:47:05Z
• Authors: Magdalena Natalia...; Radha Raman Pandey; Mateusz Mendel; David Homolka; Ravi Sachidanandam; Ramesh S. Pillai
• Keywords: Male; YTH; RNA helicase; Adenosine; Mice; 03 medical and health sciences; Protein Domains; M(6)A; MEIOC; YTHDC2; ATPase; Animals; CAHL; RNA, Messenger; Spermatogenesis; XRN1; info:eu-repo/classification/ddc/570; 0303 health sciences; DExH; Mice, Mutant Strains; Ankyrin Repeat; DNA-Binding Proteins; Meiosis; Gene Expression Regulation; Exoribonucleases; RNA Helicases

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.