Originally, we planned to use the method employed by others involving using 5'-FAM tagged primer and non-fluorescent template for the RNA extension experiments. Using this method, the template is invisible on electrophoresis gel when the gel is not stained, and only the un-extended primer and extended RNA can be observed. This was expected to simplify data analysis. However, during the course of the experiments, it was found that the fluorescence of the FAM fluorophore can be partially quenched by the RNA, and the intensity of fluorescence was highly dependent on the RNA length and sequences. Therefore, for data analysis, we mainly relied on the images obtained under UV after staining the gel with GelRed although fluorescent images without gel staining were also obtained (supporting information). It was fortunate that the fully extended 30-mer RNA 1h, which has FAM at its 5'-end, was well separated from the 30-mer RNA templates 1b-g, which does not have FAM (Figure ). with 3A, it can be seen that the modified nucleotides Ψ, m 5 C and m 6 A slightly slowed the SC2RC catalyzed RNA extension reaction. For Figure , which was obtained using template RNA 1b containing no modified nucleotides, almost all the primer molecules were consumed within 20 minutes (lane 5). For Figures , which were obtained using templates 1c-e containing Ψ, m 5 C and m 6 A, respectively, after 2 hours, a small portion of 1a could still be visible (lanes 7). These results indicate that SC2RC is sensitive to the structure variations in these modified nucleotides. However, the structure variation of the modifications are not dramatic, and for all of them, their hydrogen bonding with the incoming NTPs are canonical, and the RNA extension reactions went smoothly. The SARS-CoV-2 genome replication rate, if affected by these modifications, may contribute to the disparity of symptoms of COVID-19, but the contributions are expected to be minimal. Therefore, the difference of the epitranscriptomic machinery of different individuals for writing and erasing these modifications may have little effect on the disparity of symptoms including their severity in the context of SC2RC activity. Of course, this does not exclude other mechanisms through which these modifications exert effects. For example, m A has been demonstrated to enhance viral replication and pathogenesis, and m 6 A reader proteins YTHDF1, YTHDF2 and YTHDF3 were found to be involved in the process. The fact that SC2RC can cope with these modifications explains the feasibility for the virus to utilize them for survival in hosts via means such as RNA stabilization and immunity evasion. In comparison of Figure with 3A, it is easy to see that m 1 A had a significant negative impact on the catalytic activity of SC2RC. Even after six hours, there were still unreacted primer 1a (lane 8, Figure ). The intensity of the bands for 1a and 1h looks similar, but it is noted that 1h is a 30-mer while 1a is a 20-mer and the amounts of RNA in the bands are not proportional to the intensity of the bands. To see if there were any partially extended RNAs that overlapped with the template 1f, the gel image obtained without staining was analyzed (Figure ). Because 1f does not have FAM and thus is invisible without staining, any band that appear between 1a and 1h would be partially extended RNA. Indeed, the band corresponding to 1f in lane 1 in Figure was not visible in lane 1 in Figure , while a band with similar retention time remained in lanes 2-8 in Figure , and their intensity increased with increasing reaction time. This band must be the partially extended RNA, and it is most likely the 24-mer RNA 1i. In contrast, similar bands in the unstained gel images obtained using 1b-e as templates are not observed (supporting information).