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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Wojtas Magdalena Natalia, Pandey Radha Raman, Mendel Mateusz, Homolka David, Sachidanandam Ravi, Pillai Ramesh S.,
Project Genome protection by germline small RNAs
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Original article (peer-reviewed)

Journal Molecular Cell
Volume (Issue) 68(2)
Page(s) 374 - 387.e12
Title of proceedings Molecular Cell
DOI 10.1016/j.molcel.2017.09.021

Open Access

URL https://doi.org/10.1016/j.molcel.2017.09.021
Type of Open Access Publisher (Gold Open Access)

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.
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