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 Sep;27(9):1115-1127. doi: 10.1038/cr.2017.99. Epub 2017 Aug 15.
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.
N6-甲基腺苷（m6A）是真核 mRNA 中最常见的内部修饰。它是动态安装和去除的，并作为 mRNA 代谢的新层，调节包括干细胞多能性、细胞分化和能量稳态在内的生物过程。m6A 被选择性结合蛋白识别；YTHDF1 和 YTHDF3 协同作用影响 m6A 含有 mRNA 的翻译，YTHDF2 加速 mRNA 衰变，而 YTHDC1 影响其靶标的核处理。YTH 蛋白家族的最后一个成员 YTHDC2 的生物学功能仍然未知。我们报告 YTHDC2 选择性地在其共有基序上结合 m6A。YTHDC2 增强其靶标的翻译效率，同时降低其 mRNA 丰度。Ythdc2 敲除小鼠不育；与同窝仔相比，雄性的睾丸明显较小，雌性的卵巢明显较小。Ythdc2 敲除小鼠的生殖细胞不能发育到偶线期，因此，在减数分裂开始时，Ythdc2 在睾丸中上调。因此，YTHDC2 是一种 m6A 结合蛋白，在精子发生过程中发挥关键作用。
