Abstract
Genome instability is a double edge sword for cells, as it is the main force of evolution but also a hallmark for human diseases like cancer. For this reason, cells have finely regulated mechanisms that promote low doses of genome instability. Many of them rely on homologous recombination (HR), but their specific purposes and molecular machinery are still under investigation.Seminal work from the lab demonstrated that cells can enter mitosis with uncomplete DNA replication, and this leads to cells survival but also to increase genome instability. In this work, we studied the consequences of extended S phase in cells and demonstrated that, in these conditions, cells arrest in mitosis and perform mitotic DNA synthesis (MiDAS) via HR-related mechanism to survive. Importantly, we discovered an important player for this process, DNA polymerase α phosphorylation. This phosphorylation is essential for survival of cells with extended S phase by promoting the removal of Polα from chromatin and disruption of interactions with the replisome. Thus, we point Polα phosphorylation as part of a mechanism of replisome modeling to efficiently initiate MiDAS. Importantly, we also demonstrated that Polα phosphorylation is required for efficient meiosis, another HR-dependent mechanism, thus pointing at a general role of Polα phosphorylation in homologous recombination.We believe that a better understanding of the underlaying mechanisms that promote genome instability will help not only to better understand genome evolution, but also for situations that exploit these mechanisms like cancer cells.