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.