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

• Published in: Molecular cell Vol. 74; no. 3; pp. 494 - 507.e8
• Main Authors: Park, Ok Hyun, Ha, Hongseok, Lee, Yujin, Boo, Sung Ho, Kwon, Do Hoon, Song, Hyun Kyu, Kim, Yoon Ki
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 02.05.2019
• Subjects: CCR4-NOT complex; circular RNA; endoribonucleases; endoribonucleolytic cleavage; FTO; genes; HRSP12; m6A modification; METTL3; RNA decay; RNase P/MRP; YTHDF2; FTO; m6A modification; YTHDF2; RNase P/MRP; circular RNA; endoribonucleolytic cleavage; METTL3; RNA decay; CCR4-NOT complex; HRSP12
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2019.02.034

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. [Display omitted] •m6A-containing RNAs are degraded by an endoribonucleolytic cleavage pathway•A YTHDF2-HRSP12-RNase P/MRP axis contributes to m6A-mediated RNA decay•An interaction between YTHDF2 and RNase P/MRP is bridged by HRSP12•m6A-containing circular RNAs are degraded by the YTHDF2-HRSP12-RNase P/MRP pathway m6A-containing RNAs are known to be recognized and destabilized by YTHDF2. However, the underlying molecular mechanisms remain unclear. Park et al. show that m6A-containing linear and circular RNAs are endoribonucleolytically cleaved by a YTHDF2-HRSP12-RNase P/MRP axis.