A human high-fidelity DNA polymerase holoenzyme has a wide range of lesion bypass activities

During replication, lagging strand lesions are initially encountered by high-fidelity DNA polymerase (pol) holoenzymes comprised of pol {delta} and the PCNA sliding clamp. To proceed unhindered, pol {delta} holoenzymes must bypass lesions without stalling. This entails dNMP incorporation opposite the lesion (insertion) and the 5 template nucleotide (extension). Historically, it was viewed that high-fidelity pol holoenzymes stall upon encountering lesions, activating DNA damage tolerance pathways that are ultimately responsible for lesion bypass. Our recent study of 4 prominent lesions revealed that human pol {delta} holoenzymes support insertion and/or bypass for multiple lesions and the extents of these activities depends on the lesion and pol {delta} proofreading. In the present study, we expand these analyses to other prominent lesions. Collectively, analyses of 10 lesions from both studies reveal that the insertion and bypass efficiencies of pol {delta} holoenzymes each span a complete range (0 - 100%). Consequently, the fates of pol {delta} holoenzymes upon encountering lesions are quite diverse. Furthermore, pol {delta} proofreading promoted holoenzyme progression at 7 of the 10 lesions and did not deter progression at any. Altogether, the results significantly alter our understanding of the replicative capacity of high-fidelity pol holoenzymes and their functional role(s) in lesion bypass.