Human POLD3 coordinates leading and lagging strand mitotic DNA synthesis

Abstract

Cancer cells are characterized by the presence of oncogene-induced DNA replication stress. A common consequence of replication stress is failure to complete DNA replication in S-phase, in which case, DNA replication may be completed in mitosis by a variant of Break-Induced Replication (BIR) called Mitotic DNA Synthesis (MiDAS). POLD3, the third subunit of DNA polymerase delta, is important for BIR, although its precise role at the molecular level is unclear. Here, by mapping at high resolution newly replicated DNA at MiDAS sites, we provide novel insights into the function of POLD3. HeLa clones, with mutations targeting the PCNA-interacting domain of POLD3, demonstrate impaired synthesis of the lagging strand, suggesting that the interaction between POLD3 and PCNA facilitates the coordination of leading and lagging strand synthesis. This function of POLD3 appears to be unique to MiDAS, as DNA replication of the genome in S-phase is not affected. A better understanding of POLD3 function may help the development of novel cancer therapies targeting BIR-related pathways.