Abstract
Most DNA viruses exhibit relatively low rates of spontaneous mutation. However, the molecular mechanisms underlying DNA virus genetic stability remain unclear. In principle, mutation rates should not depend solely on polymerase fidelity, but also on factors such as DNA damage and repair efficiency. Most eukaryotic DNA viruses interact with the cellular DNA damage response (DDR), but the role of DDR pathways in preventing mutations in the virus has not been tested empirically. To address this goal, we serially transferred human adenovirus type 5 in cells in which the telangiectasia-mutated PI3K-related protein kinase (ATM), the ATM/Rad3-related (ATR) kinase, and the DNA-dependent protein kinase (DNA-PK) were chemically inactivated, as well as in control cells displaying normal DDR pathway functioning. High-fidelity deep sequencing of these viral populations revealed mutation frequencies in the order of one-millionth, with no detectable effect of the inactivation of DDR mediators ATM, ATR, and DNA-PK on adenovirus sequence variability. This suggests that these DDR pathways do not play a major role in determining adenovirus genetic diversity.
Highlights
In viruses, the rate at which new mutations are produced varies amply from 10−8 to substitutions per nucleotide per cell infection cycle (s/n/c) [1]
Access to cellular post-replicative repair is another factor that might explain the differences in mutation rate observed between DNA and RNA viruses
We found no effect of ataxia-telangiectasia-mutated PI3K-related protein kinase (ATM), ATR, and DNA-PK kinase impairment on the genetic diversity accumulated in these experimental populations, suggesting that these DNA damage response (DDR) pathways play no major role in determining adenovirus mutation rates
Summary
The rate at which new mutations are produced varies amply from 10−8 to substitutions per nucleotide per cell infection cycle (s/n/c) [1]. Within this range, the highest mutation rates (10−6 –10−4 s/n/c) correspond to RNA viruses, whereas DNA viruses mutate more slowly (10−8 –10−6 s/n/c) [2]. Knowledge of the mechanisms underlying viral mutation rates results in a better understanding of the ability of viruses to evolve, infect new hosts, and evade host cell responses. Access to cellular post-replicative repair is another factor that might explain the differences in mutation rate observed between DNA and RNA viruses. This was investigated, for instance, in Escherichia coli and 10−4
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