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Adenosine modifications impede SARS-CoV-2 RNA-dependent RNA transcription
Laura R Snyder1, Ingrid Kilde2, Artem Nemudryi3
1Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
Abstract:
SARS-CoV-2, the causative virus of the COVID-19 pandemic, follows SARS and MERS as recent zoonotic coronaviruses causing severe respiratory illness and death in humans. The recurrent impact of zoonotic coronaviruses demands a better understanding of their fundamental molecular biochemistry. Nucleoside modifications, which modulate many steps of the RNA life cycle, have been found in SARS-CoV-2 RNA, although whether they confer a pro- or antiviral effect is unknown. Regardless, the viral RNA-dependent RNA polymerase will encounter these modifications as it transcribes through the viral genomic RNA. We investigated the functional consequences of nucleoside modification on the pre-steady state kinetics of SARS-CoV-2 RNA-dependent RNA transcription using an in vitro reconstituted transcription system with modified RNA templates. Our findings show that N 6-methyladenosine and 2'-O-methyladenosine modifications slow the rate of viral transcription at magnitudes specific to each modification, which has the potential to impact SARS-CoV-2 genome maintenance.
Insights
SARS-CoV-2 RNA modifications like N6-methyladenosine and 2'-O-methyladenosine were studied. These modifications were found to slow down viral transcription, impacting SARS-CoV-2 genome maintenance.
Area of Science:
- Virology
- Molecular Biology
- Biochemistry
Background:
- Coronaviruses, including SARS-CoV-2, are significant zoonotic threats causing severe respiratory illness.
- Understanding the molecular mechanisms of coronavirus replication is crucial due to recurrent outbreaks.
- Nucleoside modifications in viral RNA can influence its life cycle, but their role in SARS-CoV-2 is unclear.
Purpose of the Study:
- To investigate the functional impact of specific nucleoside modifications on SARS-CoV-2 RNA-dependent RNA polymerase transcription kinetics.
- To determine how N6-methyladenosine and 2 -O-methyladenosine affect viral RNA synthesis.
Main Methods:
- Utilized an in vitro reconstituted transcription system.
- Employed modified RNA templates containing N6-methyladenosine and 2 -O-methyladenosine.
- Analyzed pre-steady state kinetics of SARS-CoV-2 RNA-dependent RNA transcription.
Main Results:
- N6-methyladenosine modification significantly slowed the rate of viral transcription.
- 2 -O-methyladenosine modification also reduced the rate of viral transcription.
- The magnitude of transcription rate reduction was specific to each nucleoside modification.
Conclusions:
- Nucleoside modifications in SARS-CoV-2 RNA can directly impact viral transcription efficiency.
- These modifications may play a role in regulating SARS-CoV-2 genome maintenance.
- Further research into these modifications could reveal novel antiviral strategies.
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