Grant: Operating Grant

Every few hours highly compacted chromosomes in our cells have to be unwrapped, copied, repacked and divided equally between two daughter cells. These steps have to be completed and timed exquisitely to preserve life. Indeed, mistakes during DNA replication (the process of copying the genome) lead to major chromosomal rearrangements and cell death. Our group studies the molecular mechanisms that govern DNA replication. As in life, so too in science, a picture is worth a thousand words. Using structural biology, we take pictures of the proteins that control DNA replication at work. We combine the information from these images with additional in vitro and in vivo data to understand why DNA replication occurs at a specific time of the cell cycle. In particular, we are interested on understanding how two master regulators of DNA replication, SeqA in bacteria and Dbf4 in eukaryotic cells, initiate DNA replication only when the cell is ready, pause it when replication blockages are encountered and ensure that each daughter cell ends up with the correct genetic content. Importantly, several replication protein kinases, whose activity is regulated by Dbf4, have been identified as promising anticancer drug targets. Therefore, the outcome of this research will help develop alternative approaches to target these critical kinases and will lay the foundation to understand universal regulatory mechanisms that balance the treacherous line between health and disease.