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

• Published in: Chembiochem : a European journal of chemical biology Vol. 24; no. 8; pp. e202300095 - n/a
• Main Authors: Apostle, Alexander, Yin, Yipeng, Chillar, Komal, Eriyagama, Adikari M. D. N., Arneson, Reed, Burke, Emma, Fang, Shiyue, Yuan, Yinan
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 17.04.2023
• Subjects: 5-Methylcytosine; Adenosine; Catalytic activity; COVID-19; Diabetes mellitus; epitranscriptomics; Genomes; Humans; N6-methyladenosine; Replication; Ribonucleic acid; RNA; RNA - genetics; RNA modification; RNA, Viral - genetics; RNA-dependent RNA polymerase; SARS-CoV-2; SARS-CoV-2 - genetics; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Viral diseases; COVID-19; RNA modification; SARS-CoV-2; RNA-dependent RNA polymerase; epitranscriptomics
• ISSN: 1439-4227; 1439-7633; 1439-7633
• DOI: 10.1002/cbic.202300095

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 (m5C), N6‐methyladenosine (m6A), N1‐methyladenosine (m1A) and N3‐methylcytosine (m3C) on the activity of SARS‐CoV‐2 replication complex (SC2RC). We found that Ψ, m5C, m6A and m3C had little effect, whereas 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. This fact also implies that individuals with upregulated m1A including cancer, obesity and diabetes patients might have milder symptoms. However, this contradicts clinical observations. Relevant discussions are provided. The RNA modifications Ψ, m5C and m6A have little effect on the catalytic activity of SARS‐CoV‐2 RdRp. However, although both m3C and m1A disrupt canonical base pairing, m3C can be read through by the RdRp readily, while m1A severely inhibits it.