In addition, point mutations in the catalytic ExoN residues led to coronaviruses with altered replication fidelity and a mutator phenotype, as they have 15- to 20-fold higher mutation accumulation rates. As a proofreading component, ExoN activity should contribute to the removal of misincorporated nucleotides. In fact, nsp14 ExoN activity efficiently removes a mismatched 3′-end nucleotide, mimicking an RdRp misincorporation product. At the same time, coronaviruses are relatively resistant to mutagens such as ribavirin and 5-fluorouracil, whereas coronaviruses with reduced ExoN activity are highly susceptible to these agents. These findings were the first experimental evidence supporting nsp14 ExoN activity in a coronavirus proofreading system.