Chromosome duplication is one of the most complex processes in eukaryotic cell biology, and is extremely important for our understanding of human cancer. Our cells produce a single near-perfect copy of the genetic blueprint in each cell cycle, and the duplicated sister chromatids must also inherit the same epigenetic landscape as their parents, and be held together by cohesion until mitosis. For all these reasons, the chromosome replication machinery is highly complex, and is regulated extensively by post-translational modifications. These are exciting times to study the process of chromosome duplication, the mechanism and regulation of which are highly conserved in all eukaryotic species. It is now possible to envisage projects that range from in vitro reconstitution of complex cellular processes, via cutting edge genetics and cell biology in yeast and worm embryos, to genome editing in mammalian cells by CRISPR-Cas9.
Project 1: The role of ubiquitylation in replication termination
We showed that disassembly of the replication machinery is controlled in yeast by a ubiquitin ligase and an ATPase called Cdc48 (Maric et al, Science, 2014, Maculins et al, Curr. Biol., 2015). The mechanisms and regulation remain to be elucidated, and we are now also searching for factors that regulate this process in higher eukaryotes.
Project 2: Epigenetic inheritance during chromosome replication
How do cells ensure that the epigenetic landscape is inherited faithfully when the chromosomes are unwound and duplicated? We showed that the replication machinery plays an active role in this process (Foltman et al, Cell Reports, 2013), but many fundamental questions remain unanswered. In parallel to unravelling the basic mechanisms in yeast, we aim to explore the impact of this regulation for development in higher eukaryotes, using models ranging from worm early embryos to mouse embryonic stem cells.