Chapman Group: Genome stability and DNA repair mechanisms in cancer and genome diversification
The accurate repair of DNA breaks is fundamental for protecting our genomes against cancer-causing mutations, however, the B and T lymphocytes of our immune systems deliberately induce and repair DNA breaks in a mutagenic fashion in order to adapt and diversify antigen receptor molecules. My group is interested in how cells and different tissues strike an appropriate equilibrium between accurate and mutagenic DNA repair mechanisms, so that we can understand why faults in this regulation lead to cancer, and devise innovative strategies to exploit these faults in cancer therapies.
DNA double-strand break repair in cancer and immunity:
DNA double-strand breaks (DSBs) are highly toxic and must be accurately repaired to counteract the threat of human disease and oncogenic mutations. However, in some tissues mutagenic DSB repair is actually favoured, providing a molecular mechanism by which genetic material can be transferred between genetic loci to create diversity. To cope with this intrinsic discrepancy in desired DNA repair outcome between different cellular contexts, cells have evolved complex regulatory systems that maintain an appropriate equilibrium between competing DNA repair pathways, and that ensure DNA breaks are appropriately resolved.
Recent research from the group has shown that faults in a cell's ability to establish an appropriate equilibrium between accurate and mutagenic DSB repair pathways, links the mutagenic DNA repair systems that the developing immune system uses to diversify lymphocyte antigen receptor genes, to the mutational processes that triggers the onset of common cancers harbouring deficiencies in the homologous recombination (HR) DNA repair pathway. A particular focus of our research is to understand the molecular workings of a specialised branch of the non-homologous end joining (NHEJ) DSB repair pathway governed by the 53BP1 protein. In modelling the function of this mutagenic DNA repair pathway in developing and antigen-stimulated lymphocytes, we have discovered mechanisms that are required for the repair of DNA breaks during V(D)J recombination and immunoglobulin class-switch recombination (CSR). Our group has then gone on to demonstrate that the same processes are responsible for the mutations and genomic instability that accompanies mutation/loss of the tumour suppressor gene BRCA1 in hereditary breast and ovarian cancers. Given that poly-ADP ribose polymerase (PARP) inhibitors, modern therapeutics used in the treatment of BRCA-associated cancers, exploit these DNA repair defects to selectively kill cancer cells, our group has identified mechanisms in which these compounds act, and discovered drug-resistance mechanisms that may challenge their efficacy in the clinic.