Effects of Epitranscriptomic RNA Modifications on the Catalytic Activity of 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, the modifications 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), 5methylcytosine (m5C), N6-methyladenosine (m6A), N1-methyladenosine (m1A) and N3methylcytosine (m3C) on the activity of SARS-CoV-2 replication complex (SC2RC). We found that Ψ, m5C, m6A and m3C had little effects, while m1A inhibited the enzyme. Both m1A and m3C disrupt canonical base-pairing, but they had different effects. The fact that m1A inhibits SC2RC implies that the modification can be difficult to detect. The fact also implies that individuals with upregulated m1A including cancer, obesity and diabetes patients may have milder symptoms. However, this contradicts clinical observations. Relevant discussions are provided.