Chapman group: Genome stability and DNA repair mechanisms in cancer and genome diversification
A key objective of the laboratory is to understand the context-specificity of DNA double-stranded break (DSB) repair systems, and the regulatory mechanisms that allow DNA breaks to be appropriately channelled to both accurate, and mutagenic repair outcomes between different tissues and cellular contexts.
genome integrity Laboratory
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.
Using transgenic mouse models and a combination of experimental approaches that include cell biology, molecular immunology, biochemistry, genomics and proteomics, the lab is continuing to investigate the molecular regulation and mechanisms underpinning the non-homologous end joining and homologous recombination DSB repair pathways, and the regulatory mechanisms that ensure each pathway functions in an appropriate cellular context. Ultimately, our research aims to provide a better understanding of why a breakdown in these processes results in human diseases including primary immune-deficiencies and cancer predisposition in humans.
Discovery of the 'Shieldin' DNA repair protein complex (see Ghezraoui et al. 2018 Nature). Research from the group identified Shieldin as a DNA-end protection complex and downstream component of the 53BP1 NHEJ pathway, that by stabilising single-stranded DNA termini at DNA ends catalyses their repair by NHEJ. We showed this activity to be essential for immunoglobulin class-switch recombination (CSR), its loss leading to impaired antibody production and immunodeficiency in transgenic mice deficient in the Shieldin protein REV7. We also demonstrated Shieldin to be responsible for toxic NHEJ events in BRCA1-mutant cancer cells, its loss leading to resistance to Olaparib, a clinical poly-ADP ribose polymerase (PARP) inhibitor currently being used in the clinic to treat BRCA mutant breast and ovarian cancers.
Alumni Group Members
Hind Ghezraoui - Postdoc (2015-2018)
Suzanne Snellenberg - Postdoc & Marie Skłodowska Curie Fellow (2014-2018)
Raquel Cuella-Martin - Nuffield Dept of Medicine Prize DPhil student (2014-2018)
Aleida Acampora - ERASMUS+ visiting undergraduate student (2018)
María Sanchiz - ERASMUS+ visiting undergraduate student (2017)
Elena Fueyo-Marcos - ERASMUS+ visiting undergraduate student (2017)
Yuqi Wang - NDM Summer Intern (2016)
Ziqi Chen - NDM Summer Intern (2015)
Helena Castillo Ècija - ERASMUS+ Summer Intern (2015)
Natalia Grolmusova - Final Honours School, visiting undergraduate student (2014)
Ahmed Salman - Research Assistant (2013-2014)