Endoribonucleolytic cleavage of m6A-containing RNAs by RNase P/MRP complex. Park et al.

N6-methyladenosine (m6A) is the most abundant internal modification in RNAs and plays regulatory roles in a variety of biological and physiological processes. Despite its important roles, the molecular mechanism underlying m6A-mediated gene regulation is poorly understood. Here, we show that m6A-containing RNAs are subject to endoribonucleolytic cleavage via YTHDF2 (m6A reader protein), HRSP12 (adaptor protein), and RNase P/MRP (endoribonucleases). We demonstrate that HRSP12 functions as an adaptor to bridge YTHDF2 and RNase P/MRP, eliciting rapid degradation of YTHDF2-bound RNAs. Transcriptome-wide analyses show that m6A RNAs that are preferentially targeted for endoribonucleolytic cleavage have an HRSP12-binding site and RNase P/MRP-directed cleavage site, respectively, upstream and downstream of the YTHDF2-binding site. We also find that a subset of m6A-containing circular RNAs associate with YTHDF2 in an HRSP12-dependent manner and are selectively downregulated by RNase P/MRP. Thus, our data expand the known functions of RNase P/MRP to endoribonucleolytic cleavage of m6A RNAs.N6-甲基腺嘌呤（N6-methyladenosine，m6A）是RNA中丰度最高的内部修饰，广泛参与各类生物与生理过程的调控。尽管其生物学功能至关重要，但m6A介导的基因调控的分子机制仍未被充分阐明。本研究表明，携带m6A修饰的RNA可通过YTHDF2（m6A识别蛋白）、HRSP12（衔接蛋白）以及RNase P/MRP（核糖核酸内切酶）介导的核糖体内切裂解途径被降解。研究证实，HRSP12作为衔接蛋白桥接YTHDF2与RNase P/MRP复合物，进而快速降解结合了YTHDF2的靶RNA。全转录组层面的分析显示，优先被靶向进行核糖体内切裂解的m6A RNA，其YTHDF2结合位点的上游与下游分别存在HRSP12结合位点与RNase P/MRP识别的裂解位点。此外，本研究还发现，部分携带m6A修饰的环状RNA可通过HRSP12依赖性方式与YTHDF2结合，并被RNase P/MRP选择性下调。综上，本研究结果将RNase P/MRP的已知功能范畴拓展至m6A修饰RNA的核糖体内切裂解调控。