Endoribonucleolytic cleavage of m6A-containing RNAs by RNase P/MRP complex

N6-methyladenosine (m6A) is the most abundant internal modification in RNAs, which 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 (endoribonuclease). We demonstrate that HRSP12 functions as an adaptor to bridge YTHDF2 and RNase P/MRP via its direct interactions, eliciting rapid degradation of YTHDF2-bound RNAs. Transcriptome-wide analyses reveal that HRSP12-binding site and RNase P/MRP-directed cleavage site are largely located, respectively, upstream and downstream of YTHDF2-binding site in m6A-containing RNAs. Notably, a subset of m6A-containing circular RNAs associate with YTHDF2 in a HRSP12-dependent manner and are selectively downregulated by RNase P/MRP. Thus, our data expand the role of RNase P/MRP to m6A-mediated RNA decay.N6-甲基腺嘌呤（N6-methyladenosine，m6A）是RNA中含量最丰富的内部修饰，广泛参与多种生物及生理过程的调控。尽管其功能至关重要，但m6A介导的基因调控的分子机制仍有待深入阐明。本研究发现，携带m6A修饰的RNA可通过YTHDF2（m6A识别蛋白）、HRSP12（衔接蛋白）与核糖核酸酶P/MRP（RNase P/MRP，核糖内切核酸酶）构成的复合物介导核糖内切核酸酶切割。研究证实，HRSP12可作为衔接蛋白，通过直接相互作用连接YTHDF2与RNase P/MRP，进而快速降解结合YTHDF2的RNA。全转录组分析显示，在携带m6A修饰的RNA中，HRSP12结合位点与RNase P/MRP靶向切割位点分别主要分布于YTHDF2结合位点的上游和下游区域。值得注意的是，一类携带m6A修饰的环状RNA可通过HRSP12依赖的方式与YTHDF2结合，并被RNase P/MRP选择性下调。综上，本研究数据将RNase P/MRP的功能范畴拓展至m6A介导的RNA降解途径。