Effects of Epitranscriptomic RNA Modifications on the Catalytic Activity of the SARS-CoV-2 Replication Complex

SARS-CoV-2 causes individualized symptoms. Many reasons have been given. We propose that an individual's epitranscriptomic system could be responsible as well. The viral RNA genome can be subject to epitranscriptomic modifications, which can be different for different individuals, and thus epitranscriptomics can affect many events including RNA replication differently. In this context, we studied the effects of modifications including pseudouridine (Ψ), 5-methylcytosine (m⁵ C), N6-methyladenosine (m⁶ A), N1-methyladenosine (m¹ A) and N3-methylcytosine (m³ C) on the activity of SARS-CoV-2 replication complex (SC2RC). We found that Ψ, m⁵ C, m⁶ A and m³ C had little effect, whereas m¹ A inhibited the enzyme. Both m¹ A and m³ C disrupt canonical base pairing, but they had different effects. The fact that m¹ A inhibits SC2RC implies that the modification can be difficult to detect. This fact also implies that individuals with upregulated m¹ A including cancer, obesity and diabetes patients might have milder symptoms. However, this contradicts clinical observations. Relevant discussions are provided.