N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic mRNAs and affects RNA processing and metabolism. When YTHDF2, an m6A-recognizing protein, binds to m6A, it facilitates the destabilization of m6A-containing RNAs (m6A 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 m6A RNAs. The UPF1-mediated m6A 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 m6A RNAs and highlight the multifaceted role of UPF1 in mRNA decay.
Bibliographical noteFunding Information:
We thank Dr. Ligang Wu for providing the m 6 A reporter plasmids and Drs. Akio Yamashita and Shigeo Ohno for the α-SMG6 antibody. This work was supported by a National Research Foundation ( NRF ) of Korea grant funded by the Korean government ( Ministry of Science, ICT, and Future Planning ; NRF-2015R1A3A2033665 , NRF-2018R1A5A1024261, and NRF-2022M3E5F1017965 ) and by a Korea University grant. H.H. was supported in part by the Basic Science Research Program, through the NRF, funded by the Ministry of Education ( NRF-2019R1I1A1A01058792 ). Y.L. was supported in part by the Global PhD Fellowship Program through the NRF funded by the Korean Government, South Korea.
© 2022 The Authors
- CP: Molecular biology
- RNA modification
- mRNA degradation
- nonsense-mediated mRNA decay
ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology