Past and current research
Past research has concentrated on the study of enzymes involved in DNA replication and repair by X-ray crystallography. An area of particular interest has been the helicases, enzymes which couple the energy of ATP hydrolysis to the separation of nucleic acid duplexes into their component strands. This is a fundamental requirement for many aspects of nucleic acid metabolism and mutations in various helicases have been linked to a wide variety of diseases. Our results have provided valuable insights into the mechanisms of these enzymes and demonstrated how many of the conserved motifs and structural features exhibited by helicases may be used in a larger class of ATP-powered molecular motors.

The focus of our research is now shifting to the way in which the duplicated genome is segregated during eukaryotic cell division. This complex sequence of events requires that sister chromatids are first aligned on the metaphase plate, then each sister pulled in opposite directions by the mitotic spindle during anaphase. The whole process must be tightly regulated in order to prevent deleterious errors such aneuploidy, a hallmark of many cancerous cells.

A key component of spindle apparatus is the kinetochore, a proteinaceous complex that serves to anchor the chromatids to the spindle microtubules. Not only does the kinetochore accomplish the formidable task of ensuring a stable connection between the highly dynamic microtubule and centromeric DNA, but also serves to generate the mitotic, or spindle checkpoint. This ensures that segregation does not occur until all chromatids have been correctly duplicated, aligned on the mitotic plate and attached to the appropriate microtubule. Only then may the progression in anaphase occur. The exact means by which the kinetochore senses correct attachment to the spindle remains unclear.

Future projects
We aim to determine the three-dimensional structures of some of the multi-protein complexes that comprise the kinetochore. Particular areas of interest include the proteins involved in binding centromeric DNA and the complexes implicated in generating the spindle checkpoint signal at the kinetochore. Structural information, combined with suitable functional studies should allow us to build up a model of kinetochore operation.