An accumulation of somatic and germline mutations is at the core of oncogenesis, and is often accelerated by deficiencies in genes responsible for maintaining genome integrity, such as p53 and the DNA repair proteins defective in Xeroderma pigmentosum (XP) and Bloom’s syndrome (BLM). The mechanisms involved in maintaining genome integrity and in preventing the propagation of mutant cells are extremely intricate. The DNA damage response (DDR) includes direct damage repair, recombinational repair, damage tolerance, damage-induced growth arrest and apoptosis. There is functional overlap between the different branches of the DDR, so that (for example) double-stranded DNA breaks can be repaired either by end-joining or by homologous recombination, depending on the circumstances. Because of their deficiencies in DDR, some cancer cells may be strongly dependent on the remaining pathways to maintain a functioning genome under conditions of rapid replication and chemical stress. These considerations suggest that inhibiting DDR processes may be a new avenue in cancer therapy. Our group aims to test this hypothesis and to promote the understanding of DDR processes using structural and chemical biology.
The second area of research focusses on the consequences of genetic instability: the impact of mutations on human disease. Vast studies in genetic associations and genomic sequencing are continuously adding to the list of mutations and variations associated with disease. In many cases, the roles of the mutated genes remain obscure. We initiate research on novel disease-linked genes by expressing and purifying the proteins, and attempting to decipher their functions by a combination of structural studies, biochemical assays, and the use of antibodies to locate the proteins in cells and tissues.