UPF1 promotes rapid degradation of m6A-containing RNAs

N-6-methyladenosine (m(6)A) is the most prevalent internal modification in eukaryotic mRNAs and affects RNA processing and metabolism. When YTHDF2, an m(6)A-recognizing protein, binds to m(6)A, it facilitates the destabilization of m(6)A-containing RNAs (m(6)A RNAs). Here, we demonstrate that upstream frameshift 1 (UPF1), a key factor for nonsense-mediated mRNA decay, interacts with YTHDF2, thereby triggering rapid degradation of m(6)A RNAs. The UPF1-mediated m(6)A RNA degradation depends on a specific interaction between UPF1 and N-terminal residues 101-168 of YTHDF2. UPF1 ATPase/helicase activities, and UPF1 interaction with proline-rich nuclear receptor coactivator 2 (PNRC2), a decapping-promoting factor preferentially involved in nonsense-mediated mRNA decay. Furthermore, transcriptome-wide analyses show that YTHDF2-bound mRNAs that are not substrates for HRSP12-RNase P/MRP-mediated endoribonucleolytic cleavage are destabilized with a higher dependency on UPF1. Collectively, our data indicate dynamic and multilayered regulation of the stability of m(6)A RNAs and highlight the multifaceted role of UPF1 in mRNA decay.

Automated summary

This study reveals the interaction between UPF1 and YTHDF2, leading to rapid degradation of m(6)A RNAs. UPF1 mediates the degradation of m(6)A RNAs through a specific interaction with the N-terminal residues of YTHDF2 and interaction with PNRC2. Transcriptome-wide analyses show that mRNAs bound to YTHDF2 undergo destabilization with a higher dependency on UPF1. These findings highlight the dynamic and multilayered regulation of m(6)A RNA stability and the multifaceted role of UPF1 in mRNA decay.