Shi Hailing, Wang Xiao, Lu Zhike, Zhao Boxuan S, Ma Honghui, Hsu Phillip J, Liu Chang, He Chuan
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Cell Res. 2017 Mar;27(3):315-328. doi: 10.1038/cr.2017.15. Epub 2017 Jan 20.
N-methyladenosine (mA) is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in cell differentiation and tissue development. It regulates multiple steps throughout the RNA life cycle including RNA processing, translation, and decay, via the recognition by selective binding proteins. In the cytoplasm, mA binding protein YTHDF1 facilitates translation of mA-modified mRNAs, and YTHDF2 accelerates the decay of mA-modified transcripts. The biological function of YTHDF3, another cytoplasmic mA binder of the YTH (YT521-B homology) domain family, remains unknown. Here, we report that YTHDF3 promotes protein synthesis in synergy with YTHDF1, and affects methylated mRNA decay mediated through YTHDF2. Cells deficient in all three YTHDF proteins experience the most dramatic accumulation of mA-modified transcripts. These results indicate that together with YTHDF1 and YTHDF2, YTHDF3 plays critical roles to accelerate metabolism of mA-modified mRNAs in the cytoplasm. All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to mA RNA methylation.
N6-甲基腺苷（m6A）是真核生物信使核糖核酸（mRNA）中最丰富的内部修饰，在细胞分化和组织发育中发挥重要作用。它通过选择性结合蛋白的识别，在RNA生命周期的多个步骤中发挥调节作用，包括RNA加工、翻译和降解。在细胞质中，m6A结合蛋白YTHDF1促进m6A修饰的mRNA的翻译，而YTHDF2加速m6A修饰的转录本的降解。YTHDF3是YTH（YT521-B同源）结构域家族的另一种细胞质m6A结合蛋白，其生物学功能尚不清楚。在此，我们报道YTHDF3与YTHDF1协同促进蛋白质合成，并影响通过YTHDF2介导的甲基化mRNA降解。缺乏所有三种YTHDF蛋白的细胞中，m6A修饰的转录本积累最为显著。这些结果表明，YTHDF3与YTHDF1和YTHDF2一起，在加速细胞质中m6A修饰的mRNA的代谢方面发挥关键作用。所有三种YTHDF蛋白可能以整合和协同的方式发挥作用，以影响与m6A RNA甲基化相关的基本生物学过程。
