Previous and current research
Chromosomal double-strand breaks (DSBs) represent one of the most disrupting forms of DNA damage. They can be induced by exogenous agents, such as ionizing radiation or anti-cancer drugs, or by endogenous agents such as free radicals generated from oxidative metabolism. Naturally occurring DSBs are used by the immune system to generate antibody diversity, and by meiotic cells to facilitate genetic diversity through homologous recombination. Efficient double-strand break repair is essential for the survival of each cell because unrepaired breaks can lead to chromosome fragmentation and cellular death, and improperly repaired breaks lead to mutations, chromosomal translocations and cancer.

To preserve genomic integrity, DNA double-strand breaks are repaired in eukaryotes by two distinct mechanisms: RAD52-dependent homologous recombination (HR) and Ku-dependent non-homologous end joining (NHEJ). Although these pathways provide alternative functions in mammalian somatic cells, germ-line cells utilise HR as the major pathway for DSB repair. We would like to understand exactly how these repair mechanisms take place and what cellular factors determine the choice of repair pathway.

Future projects
To understand how genetic recombination promotes the reassortment of genes at meiosis, and how the cell utilises genetic recombination as a means to repair damaged or broken DNA molecules, we have purified and investigated the properties of several of the key proteins involved in recombination. In vitro systems for the formation of recombinant DNA by the human RAD51, RAD52 and RP-A proteins have been developed, and studies of newly identified recombination proteins such as RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 are now in progress.

In recent work we have shown that BRCA2, defects in which are linked to inheritable breast and ovarian cancers, interacts specifically with the RAD51 recombinase and controls its activity in response to DNA damaging agents. This involvement of BRCA2 in homologous recombination is likely to account for the genomic instability phenotype and DNA repair defects associated with BRCA2. Further understanding of the interplay between BRCA2 and RAD51, and other partner recombination proteins, will allow us to understand how the genome is maintained in a stable state and how defects in these processes lead to cancer predisposition.