Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis

Abstract

N-methyladenosine (mA) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. mA is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of mA-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds mA at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knockout mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those of littermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and accordingly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an mA-binding protein that plays critical roles during spermatogenesis.

Viral and cellular N6-methyladenosine and N6,2′-O-dimethyladenosine epitranscriptomes in the KSHV life cycle

“…4c). These results could be due to other reader proteins such as YTHDF1, YTHDF3 and YTHDC2, which redundantly mediate m 6 A/m-dependent mRNA stability 21,22,26 . These reader proteins might compensate its function following YTHDF2 knockdown.…”

“…In addition, YTHDF3, cooperates with either YTHDF1 or YTHDF2 to promote translation or degradation of transcripts, respectively 23,24 . YTHDC1 has been implicated in splicing whereas YTHDC2 is implicated in both translation and degradation 25,26 .…”

METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m 6 A‐YTHDF2–dependent manner

“…The effect of m 6 A modification on mRNA transcripts is mediated by specific m 6 A binding proteins, which are also known as m 6 A readers (24). The YTH domain family proteins YTHDF1-3 and YTH domain containing 1-2 have been identified as m 6 A-binding proteins in mammals (35,36,46,59). YTHDF2 recognizes and destabilizes m 6 A-containing mRNA (35), whereas YTHDF1 and YTHDF3 regulate mRNA translation and promote protein synthesis (37,38).…”

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…showed that YTH domain family protein 3 (YTHDF3) promoted translation in synergy with YTHDF1 and affected methylated mRNA decay mediated through YTHDF2 30. And recently, researchers have found that YTHDC2 promotes translation efficiency and decreases the mRNA abundance 31. Apart from the YTH domain family, certain proteins in the heterogeneous nuclear ribonucleoprotein family also act as “readers”.…”