m(1)A and m(6)A modifications function cooperatively to facilitate rapid mRNA degradation

Abstract

N-6-Methyladenosine (m(6)A), the most abundant internal mRNA modification, affects multiple steps in gene expression. Mechanistically, the binding of YTHDF2 to m(6)A on mRNAs elicits rapid mRNA degradation by re-cruiting several RNA degrading enzymes. Here, we show that N-1-methyladenosine (m(1)A), another type of RNA modification, accelerates rapid m(6)A RNA degradation. We identify HRSP12 as an RNA-binding protein that recognizes m(1)A. The binding of HRSP12 to m(1)A promotes efficient interaction of YTHDF2 with m(6)A, consequently facilitating endoribonucleolytic cleavage via the RNase P/MRP complex. Transcriptomewide analyses also reveal that mRNAs harboring both m(1)A and m(6)A are downregulated in an HRSP12-dependent manner compared with mRNAs harboring m(6)A only. Accordingly, a subset of endogenous circular RNAs that harbor m(6)A and associate with YTHDF2 in an HRSP12-dependent manner is also subjected to m(1)A-facilitated rapid degradation. Together, our observations provide compelling evidence for crosstalk between different RNA modifications.