How can the inherent defects in chromosome replication that characterise many cancer cells be exploited therapeutically? One of the most important and complex challenges for any cell is to copy the genome before cell division. The scale of the challenge is enormous, and eukaryotic chromosome replication is particularly complex and fascinating, since it involves many other processes in addition to DNA synthesis, such as chromatin regeneration, the establishment of cohesion between the newly formed sister chromatids, and a myriad of DNA repair processes.
Our lab studies the large multi-protein machine known as the replisome, which is the central player in the process of chromosome duplication at DNA replication forks. The assembly and disassembly of the replisome are regulated extensively by post-translational modifications, ensuring that the replisome makes just one copy of each chromosome per cell cycle.
We recently discovered that replisome disassembly requires the Cdc48 ‘segregase' and is regulated by a ubiquitylation pathway at the end of chromosome replication. We found that yeast and metazoa use different E3 ligases to ubiquitylate the DNA helicase that forms the core of the replisome. Moreover, metazoa have a second pathway for replisome disassembly that acts during mitosis, requiring a factor that is mutated in various human cancers. This suggests that a deeper understanding of replisome disassembly is likely to identify interesting new targets for future therapies.