DNA Damage Response Laboratory
Previous and current research
DNA can be damaged in many different ways and must be repaired correctly to prevent loss of vital genetic information. DNA damage response (DDR) pathways have evolved to sense, signal and repair all types of DNA lesion that can occur. The importance of such pathways in maintaining genomic integrity is highlighted by inherited cancer predisposition syndromes, such as Li-Fraumeni and xeroderma pigmentosum that are caused by mutations in DDR genes. We are focusing on understanding the DNA repair functions of the breast and ovarian cancer tumour suppressor genes BRCA1 and BRCA2 and their relationship with the Fanconi anaemia (FA) pathway.
We have recently identified functional orthologues of the BRCA and FA tumour suppressor genes in the nematode C. elegans and are exploiting the powerful genetics, cytology and biochemistry of this organism to elucidate the role of these genes in DNA repair and signalling processes. To this end we have isolated deletion mutants in brc-1 (BRCA1), brd-1 (BARD1), brc-2 (BRCA2) and fcd-2 (FANCD2) in the nematode and are investigating their roles in DNA repair and meiotic recombination. In order to gain insight into how the protein products of these genes function in vivo we are also analysing their spatial, temporal and sub-cellular localisation by immunofluorescence and analysis of transgenic lines. Furthermore, we have recently described a standardised method for purifying associated protein complexes that enables us to identify novel protein interaction partners in vivo. We have successfully purified protein complexes associated with BRC-1, BRC-2 and FCD-2 and are currently investigating the roles of a number of novel interacting partners in repair and recombination processes.
Future research
In the future, we aim to further define the roles of the BRCA and FA pathways in DDR process by genetic and biochemical means in C. elegans. Insights gained in the nematode will be used to analyse these pathways in complex eukaryotes potentially using mouse models and cell culture techniques.
