The molecular machinery that cells use to duplicate chromosomes has been conserved remarkably well during the evolution of eukaryotes. This means that almost all replisome components have a single orthologue in each species. It is very important to understand the mechanisms of chromosome replication in human cells, because defects in replication drive cancer development and provide opportunities for novel therapies. But almost all of our knowledge of chromosome duplication in human cells comes from more powerful model systems, particularly the budding yeast Saccharomyces cerevisiae (and the fission yeast Schizosaccharomyces pombe), together with the frog Xenopus laevis. In general, the fastest way to learn how chromosomes are copied in human cells is to study yeast!
For several reasons, however, we also study aspects of chromosome duplication directly in higher eukaryotes. Rather than simply confirming what we have found in yeast (we don’t want to reinvent the wheel), the idea is to use other species when we have an interesting question that can only be answered in that way, or when there is evidence that higher eukaryotes genuinely do things differently for some reason. To screen for factors that regulate chromosome replication in vivo in higher eukaryotes, we are using the early embryo of the nematode Caenorhabditis elegans, which provides a unique opportunity to deplete proteins by RNA interference during meiosis, so that the phenotype can then be studied in the first embryonic cell cycle. New insights from worms can then be tested in vertebrate model systems. One approach uses extracts of frog eggs to study chromosome replication in vitro (collaboration with Dr. Aga Gambus, University of Birmingham). In addition, we work with mouse embryonic stem cells, which are stable diploid cells that can be modified by CRISPR-Cas9, differentiated in vitro into a range of cell types, and have a replication machinery that is essentially identical to humans.