Previous and current research
Sister chromatids, the products of eukaryotic genome replication, are held together by the chromosomal 'cohesin' complex after their synthesis. This allows the mitotic spindle in metaphase to recognise pairs of replication products for segregation into opposite directions. At anaphase onset, sister chromatids start to move synchronously and irreversibly into opposite halves of the dividing cell, pulled by the mitotic spindle. Faithful segregation of sister chromatids is crucial for cells to prevent aneuploidy, an incidence of missing or supernumerous chromosomes that is a hallmark of malignant tumours. Our research focuses on how cells pack their duplicated genome into sister chromatids in metaphase, and how these sister chromatids are separated and securely moved into daughter cells in anaphase.

Future projects
Cohesin forms large protein rings that may bind chromosomes by encircling DNA strands. We are now studying how cohesion between sister chromatids is established during DNA replication. Does the replication fork slide through the cohesin ring, thereby ensuring that replication products are always trapped inside the same ring? How do auxiliary cohesion establishment proteins contribute? At anaphase onset a protease is activated that we have identified and called 'separase'.

Separase cleaves the Scc1 subunit of cohesin, leading to opening of the cohesin ring to trigger sister chromatid segregation. We study the mechanisms that regulate the activity of separase such that cleavage of cohesin is timely and efficient, but never happens prematurely. Is cohesin cleavage the only trigger for anaphase and high fidelity chromosome segregation? We have found that separase not only cleaves cohesin but at the same time activates a protein phosphatase, called Cdc14. This phosphatase in turn is required for stable elongation of the anaphase spindle. We are now investigating how separase activates the Cdc14 phosphatase, and how this orchestrates the execution of the anaphase programme. Most of these studies use the budding yeast Saccharomyces cerevisiae as a model. Cohesin and separase regulate chromosome segregation also in higher eukaryotes, including man, making these studies important in a broad context.