2024/05/24 by Matthias Becker, Matthias A. Becker, Nathalie Meiser +6
Biochemistry, Genetics and Molecular Biology · #Cancer-related gene regulation #Epigenetics and DNA Methylation #RNA modifications and cancer
paper · pdf · doi:10.1002/chem.202401897
openalex publication_date 2024/05/24 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
Abstract The SARS‐CoV‐2 genome has been shown to be m 6 A methylated at several positions in vivo . Strikingly, a DRACH motif, the recognition motif for adenosine methylation, resides in the core of the transcriptional regulatory leader sequence (TRS−L) at position A74, which is highly conserved and essential for viral discontinuous transcription. Methylation at position A74 correlates with viral pathogenicity. Discontinuous transcription produces a set of subgenomic mRNAs that function as templates for translation of all structural and accessory proteins. A74 is base‐paired in the short stem‐loop structure 5’SL3 that opens during discontinuous transcription to form long‐range RNA‐RNA interactions with nascent (−)‐strand transcripts at complementary TRS‐body sequences. A74 can be methylated by the human METTL3/METTL14 complex in vitro . Here, we investigate its impact on the structural stability of 5’SL3 and the long‐range TRS‐leader:TRS‐body duplex formation necessary for synthesis of subgenomic mRNAs of all four viral structural proteins. Methylation uniformly destabilizes 5’SL3 and long‐range duplexes and alters their relative equilibrium populations, suggesting that the m 6 A74 modification acts as a regulator for the abundance of viral structural proteins due to this destabilization.