Cytoplasmic N6-methyl-adenosine (m6A) Reader YTHDF3 Promotes mRNA Translation
N6-methyl-adenosine (m6A) is one of the most common and abundant modifications on RNA molecules present in eukaryotes. m6A methylation is catalyzed by a multicomponent methyltransferase complex composed of at least three subunits: METTL3, METTL14 and WTAP, removed by demethylases FTO and ALKBH5, and recognized by YTH-domain containing readers. Cytoplasmic readers YTHDF1 and YTHDF2 were demonstrated to modulate mRNA translation and stability, respectively, and nuclear reader YTHDC1 was revealed to regulate m6A-dependent mRNA splicing. However, the detailed function of another cytoplasmic reader YTHDF3 remains unknown.
The lab of Prof. YANG Yungui from Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, revealed that the cytoplasmic m6A reader YTHDF3 promotes mRNA translation in cooperation with YTHDF1, the work has been published online in Cell Research on January 20.
Their study identified direct interaction betweenYTHDF3 and ribosomal 40S and 60S subunits. They further performed in vivo quantitative assay of nascent protein synthesis and demonstrated that YTHDF3 promotes the translation of targeted m6A-methylated mRNAs. Moreover, in combination with PAR-CLIP, western blotting assay and bioinformatics analysis, they revealed that YTHDF3 significantly regulates translation of YTHDF1/3 common targets, but not YTHDF3 unique targets, suggesting that YTHDF3 and YTHDF1 may cooperate in translation regulation. Collectively, these data provide the direct evidence that the cytoplasmic m6A reader YTHDF3 promotes mRNA translation through interacting with ribosomal proteins, in cooperation with YTHDF1.
Cell Research also published the research of Prof. HE Chuan (University of Chicago) about YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA in the same issue. These findings illustrate the molecular mechanism of m6A reader YTHDF3 regulating mRNA translation, providing the basis for the further study on biological function of m6A and epitranscriptomics,.
This research is supported by Ministry of Science and Technology, Natural Science Foundation of China, and CAS Strategic Priority Research Programs.
YTHDF3 promotes mRNA translation (Image by YANG Yungui's lab)
Contact:
Prof. YANG Yungui
CAS Key Laboratory of Genomic and Precision Medicine
E-mail: ygyang@big.ac.cn
