mA and mA modifications function cooperatively to facilitate rapid mRNA degradation.

N-Methyladenosine (mA), the most abundant internal mRNA modification, affects multiple steps in gene expression. Mechanistically, the binding of YTHDF2 to mA on mRNAs elicits rapid mRNA degradation by recruiting several RNA degrading enzymes. Here, we show that N-methyladenosine (mA), another type of RNA modification, accelerates rapid mA RNA degradation. We identify HRSP12 as an RNA-binding protein that recognizes mA. The binding of HRSP12 to mA promotes efficient interaction of YTHDF2 with mA, consequently facilitating endoribonucleolytic cleavage via the RNase P/MRP complex. Transcriptome-wide analyses also reveal that mRNAs harboring both mA and mA are downregulated in an HRSP12-dependent manner compared with mRNAs harboring mA only. Accordingly, a subset of endogenous circular RNAs that harbor mA and associate with YTHDF2 in an HRSP12-dependent manner is also subjected to mA-facilitated rapid degradation. Together, our observations provide compelling evidence for crosstalk between different RNA modifications.