Endoribonucleolytic Cleavage of m6A-Containing RNAs by RNase P/MRP Complex

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 a RNase P/MRP-directed cleavage site upstream and downstream of the YTHDF2-binding site, respectively. We also find that a subset of m⁶A-containing circular RNAs associates with YTHDF2 in an HRSP12-dependent manner and is selectively downregulated by RNase P/MRP. Thus, our data expand the known functions of RNase P/MRP to endoribonucleolytic cleavage of m⁶A RNAs.

CCR4-NOT complex; FTO; HRSP12; METTL3; RNA decay; RNase P/MRP; YTHDF2; circular RNA; endoribonucleolytic cleavage; m(6)A modification.