DNA polymerase ε relies on a unique domain for efficient replisome assembly and strand synthesis

• DOI: 10.1038/s41467-020-16095-x
• Publication Date: 2020-05-15T10:05:00Z
• Authors: Xiangzhou Meng; Lei Wei; Sujan Devbhandari; Tuo Zhang; Jenny Xiang; Dirk Remus; Xiaolan Zhao
• Keywords: DNA Replication; 0303 health sciences; Saccharomyces cerevisiae Proteins; Genome, Human; Science; Q; Cell Cycle; Cell Cycle Proteins; DNA Polymerase II; Saccharomyces cerevisiae; Article; 03 medical and health sciences; Chromosome Structures; Gene Expression Regulation; Protein Domains; Doxycycline; Neoplasms; Mutation; Humans; Poly-ADP-Ribose Binding Proteins

AbstractDNA polymerase epsilon (Pol ε) is required for genome duplication and tumor suppression. It supports both replisome assembly and leading strand synthesis; however, the underlying mechanisms remain to be elucidated. Here we report that a conserved domain within the Pol ε catalytic core influences both of these replication steps in budding yeast. Modeling cancer-associated mutations in this domain reveals its unexpected effect on incorporating Pol ε into the four-member pre-loading complex during replisome assembly. In addition, genetic and biochemical data suggest that the examined domain supports Pol ε catalytic activity and symmetric movement of replication forks. Contrary to previously characterized Pol ε cancer variants, the examined mutants cause genome hyper-rearrangement rather than hyper-mutation. Our work thus suggests a role of the Pol ε catalytic core in replisome formation, a reliance of Pol ε strand synthesis on a unique domain, and a potential tumor-suppressive effect of Pol ε in curbing genome re-arrangements.