PRJNA561356
Human adenovirus type 5 experimental evolution in MRC-5 cells in absence of ATM, ATR and DNA-PK pathways functioning
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 with chemically-inactivated DDRATM, ATR and DNA-PK kinases, as well as in control cells displaying normal DDR pathways functioning. High-fidelity deep sequencing of these viral populations revealed mutation frequencies on the order of one millionth, with no detectable effect of the DDR inactivation of these DDR mediators on adenovirus sequence variability. This suggests that DDR ATM, ATR and DNA-PK pathways does not play a major role in determining adenovirus genetic diversity.