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

Xiangzhou Meng, Lei Wei, Sujan Devbhandari, Tuo Zhang, Jenny Xiang, Dirk Remus and Xiaolan Zhao ()
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Xiangzhou Meng: Memorial Sloan Kettering Cancer Center
Lei Wei: Memorial Sloan Kettering Cancer Center
Sujan Devbhandari: Memorial Sloan Kettering Cancer Center
Tuo Zhang: Weill Cornell Medical College
Jenny Xiang: Weill Cornell Medical College
Dirk Remus: Memorial Sloan Kettering Cancer Center
Xiaolan Zhao: Memorial Sloan Kettering Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract DNA 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.

Date: 2020
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DOI: 10.1038/s41467-020-16095-x

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