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

Abstract

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

N6-Methyladenosine Role in Acute Myeloid Leukaemia

“…YTHDC2 has a dual role in controlling the expression of m 6 A modified mRNAs, it both enhances their translation and accelerates their decay [39,40,41]. In contrast to the other YTH proteins, YTHDC2 contains other functional regions in addition to the YTH domain, including an ATP-dependent RNA helicases domain interspersed with two Ankyrin repeats, a known protein–protein interaction module that is responsible for the recruiting of the Xrn1 exoribonuclease [39,40,41].…”

“…In contrast to the other YTH proteins, YTHDC2 contains other functional regions in addition to the YTH domain, including an ATP-dependent RNA helicases domain interspersed with two Ankyrin repeats, a known protein–protein interaction module that is responsible for the recruiting of the Xrn1 exoribonuclease [39,40,41]. In mouse, the protein is highly expressed in germ cells and is essential for male and female fertility.…”

“…In mouse, the protein is highly expressed in germ cells and is essential for male and female fertility. It has been suggested that the binding of YTHDC2 can accelerate protein synthesis, as well as rapid mRNA decay, to timely regulate gene expression during cell differentiation and developmental programs [39,40,41]. …”

Flexible binding of m6A reader protein YTHDC1 to its preferred RNA motif

“…Wang et al, 2015), while highly similar YTHDF2 reader controls destabilization of cellular transcripts by targeting them to P-bodies (X. . The nuclear reader YTHDC1 plays a role in splicing regulation (Xiao et al, 2016), while YTHDC2 contains additional RNAse helicase domain and is important in meiosis (Wojtas et al, 2017).…”

An additional class of m6A readers

“…The functions of m 6 A are mediated by RNA binding proteins that selectively bind to m 6 A-containing RNAs, called m 6 A reader proteins. The m 6 A reader proteins characterized to date recognize m 6 A-containing RNAs either by using a YT521-B homology (YTH) domain to directly bind the m 6 A base 1,2 , or by binding to single-stranded RNA motifs that become exposed upon m 6 A-induced changes in RNA structure 3,4 . On page xxx of this issue, Huang et al 5 discover an additional class of m 6 A reader proteins that use K Homology (KH) domains to selectively recognize m 6 A-containing RNAs and promote their translation and stability.…”