UPF1 promotes rapid degradation of m6A-containing RNAs

Sung Ho Boo, Hongseok Ha, Yujin Lee, Min Kyung Shin, Sena Lee, Yoon Ki Kim

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number110861
JournalCell Reports
Volume39
Issue number8
DOIs
Publication statusPublished - 2022 May 24

Bibliographical note

Funding 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.

Publisher Copyright:
© 2022 The Authors

Keywords

  • CP: Molecular biology
  • N6-methyladenosine
  • PNRC2
  • RNA modification
  • UPF1
  • YTHDF2
  • mA
  • mRNA degradation
  • nonsense-mediated mRNA decay

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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