UPF1 promotes rapid degradation of m6A-containing RNAs

N6-methyladenosine (m6A) is the most prevalent internal modification in the eukaryotic mRNAs, affecting many facets of RNA processing or metabolism. In particular, m6A-containing RNAs (m6A RNAs) are rapidly degraded via an m6A-binding protein, YT521-B homology domain-containing family protein 2 (YTHDF2). Here, we demonstrate that UPF1 (a key factor for nonsense-mediated mRNA decay) interacts with YTHDF2, triggering rapid degradation of m6A RNAs. The UPF1-mediated m6A RNA degradation requires an interaction between UPF1 and the N-terminal 101-200 residues in YTHDF2. Our complementation experiments reveal that the m6A RNA degradation requires ATPase/helicase activities of UPF1 and an interaction of UPF1 with PNRC2 (a decapping promoting factor). Transcriptome-wide analyses show that the UPF1-mediated m6A RNA degradation pathway preferentially targets mRNAs containing YTHDF2-binding sites (or m6As) in the 3UTR. Collectively, our data provide dynamic and multilayered regulation of the stability of m6A RNAs.