m6A Methylation of Transcription Leader Sequence of SARS-CoV-2 Impacts Discontinuous Transcription of Subgenomic mRNAs.
Chemistry
; 30(42): e202401897, 2024 Jul 25.
Article
in En
| MEDLINE
| ID: mdl-38785102
ABSTRACT
The SARS-CoV-2 genome has been shown to be m6A methylated at several positions inâ
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 inâ
vitro. Here, we investigate its impact on the structural stability of 5'SL3 and the long-range TRS-leaderTRS-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 m6A74 modification acts as a regulator for the abundance of viral structural proteins due to this destabilization.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription, Genetic
/
RNA, Messenger
/
RNA, Viral
/
Adenosine
/
SARS-CoV-2
/
Methyltransferases
Limits:
Humans
Language:
En
Journal:
Chemistry
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: