Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
Cell Rep. 2022 Sep 6;40(10):111317. doi: 10.1016/j.celrep.2022.111317.
N-Methyladenosine (mA), the most abundant internal mRNA modification, affects multiple steps in gene expression. Mechanistically, the binding of YTHDF2 to mA on mRNAs elicits rapid mRNA degradation by recruiting several RNA degrading enzymes. Here, we show that N-methyladenosine (mA), another type of RNA modification, accelerates rapid mA RNA degradation. We identify HRSP12 as an RNA-binding protein that recognizes mA. The binding of HRSP12 to mA promotes efficient interaction of YTHDF2 with mA, consequently facilitating endoribonucleolytic cleavage via the RNase P/MRP complex. Transcriptome-wide analyses also reveal that mRNAs harboring both mA and mA are downregulated in an HRSP12-dependent manner compared with mRNAs harboring mA only. Accordingly, a subset of endogenous circular RNAs that harbor mA and associate with YTHDF2 in an HRSP12-dependent manner is also subjected to mA-facilitated rapid degradation. Together, our observations provide compelling evidence for crosstalk between different RNA modifications.
N6-甲基腺苷（m6A）是最丰富的内部 mRNA 修饰物，影响基因表达的多个步骤。从机制上讲，YTHDF2 与 mRNA 上的 m6A 结合会通过招募几种 RNA 降解酶来迅速引发 mRNA 降解。在这里，我们发现另一种 RNA 修饰物 N6-甲基腺苷（m6A）会加速 m6A RNA 的快速降解。我们鉴定出 HRSP12 是一种识别 m6A 的 RNA 结合蛋白。HRSP12 与 m6A 的结合促进了 YTHDF2 与 m6A 的有效相互作用，从而通过 RNase P/MRP 复合物促进内切核酸酶切割。全转录组分析还显示，与仅含有 m6A 的 mRNA 相比，含有 m6A 和 m6A 的 mRNA 以 HRSP12 依赖的方式下调。因此，一组含有 m6A 并与 HRSP12 相关的内源性环状 RNA 也受到 m6A 促进的快速降解。总之，我们的观察结果为不同 RNA 修饰之间的串扰提供了有力的证据。
