2024-11-18

Abstract：

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 employed our recently developed method, Polymerase-usage sequencing (Pu-seq), to map the global usage of replicative polymerases (Pol ε and Pol α) as well as error-prone DNA polymerases (Pol η and Pol κ) in HCT116 cells. 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.

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