Previous and current research
Chromosomal instability is one of the classic signatures of tumorigenesis and tumour progression. There are many factors that can generate chromosome damage, including exogenous agents, such as ionising radiation, and endogenous reactive oxygen species. Moreover, DNA metabolism itself is not always executed perfectly and cells require mechanisms for correcting these imperfections and for ensuring that DNA replication and chromosome segregation are executed faithfully. Our previous studies have focused on defining DNA repair mechanisms for removal of oxidative DNA damage, and on the roles of DNA topoisomerases in genetic recombination and chromosome segregation. As part of these studies, we identified a eukaryotic RecQ-like DNA helicase, Sgs1, that forms a complex with at least two DNA topoisomerases and is necessary for the prevention of reckless homologous recombination and chromosome missegregation. Sgs1 is closely related to BLM, the gene defective in the disorder Bloom's Syndrome, in which individuals show inherent genomic instability and a highly elevated cancer incidence. We have focused the majority of our recent effort on an analysis of the functional roles of the BLM protein.

Future projects
We aim to understand at the molecular level how the cellular complex comprising RecQ-like proteins and DNA topoisomerases functions to prevent excessive genetic recombination and defects in chromosome segregation. We will seek to identify and characterise additional components that operate in concert with these proteins. One interacting partner is RAD51, which plays a central role in homologous recombination. Another important partner is BLAP75/hRMI1, which appears essential for the stability of a multi-enzyme complex containing BLM.

Studies have been initiated to explore the idea that this protein complex is required for efficient recombinational repair at sites of stalled DNA replication. The regulation of BLM function by stress-activated kinases, particularly ATM and ATR, is also being analysed. A second major area of future interest is to exploit the cloning and structural characterisation of two human genes required for the base excision repair pathway. Chemical inhibitors of DNA repair are being characterised, which we hope will have utility as radiation- and/or chemo-sensitizers in the treatment of human cancer.