'Error-prone DNA polymerases: functions and mutagenic consequences during genome replication '

DNA replication is the mechanism underlying genetic inheritance, and its accuracy and efficiency are crucial for all organisms. In humans, loss of replication fidelity causes inherited syndromes and somatic diseases, such as cancer. Eukaryotes have 16 different DNA polymerases, each with distinct fidelity and efficiency in their synthetic activities. Therefore, the division of labour among these polymerases is a key factor in maintaining genome stability during replication. To investigate the roles of various polymerases in genome replication, we currently investigate global usage of various DNA polymerases including major replicative polymerases (Pol α, Pol δ and Pol ε) and error-prone DNA polymerases (Pol η, Pol κ etc.) in multiple human cell lines. By analysing the profiles of these polymerases, alongside canonical assignments of replicative polymerases to leading and lagging strand replication, we identified the contribution of error-prone polymerases to lagging strand replication. Although this contribution is smaller, it is still appreciably detectable. We currently hypothesise that the stochastic usage of these error-prone polymerases may contribute to mutational strand asymmetry around replication initiation sites. Furthermore, by comparing the profiles of DNA polymerases with genome-wide mutation patterns in various cancers, we discuss the significance of DNA polymerase dynamics in shaping the mutational landscapes of these cancers.

Bainbridge et al https://doi.org/10.1101/2025.09.10.675280 2025

Koyanagi et al Nat Commun 13, 7221 2022