Every time a human cell divides, its DNA must be copied perfectly—and that process constantly creates tiny breaks and errors that, if left unrepaired, can lead to cancer. This research tackles a fundamental gap in biology: how do cells choose the right repair method at the right moment? The main high-fidelity repair system, called homologous recombination (HR), is driven by a protein called Rad51. But Rad51 can either protect or destabilise the genome depending on how it is switched on. The project will unpick two control mechanisms—one involving the well-known BRCA tumour suppressor complex, and another, newly discovered pathway triggered by a protein called Plk1. The team will use advanced proteomics to find the molecules that govern this second pathway, and high-resolution DNA mapping to see exactly where repair proteins bind across the genome. This is fundamental science. It will not produce a drug or a diagnostic test tomorrow. But understanding how genome repair is regulated is essential groundwork. Similar fundamental work on DNA repair pathways has already led directly to PARP inhibitors, a class of cancer drugs that exploit repair defects in tumours. A clearer picture of HR regulation could eventually reveal new targets for treating cancers and other diseases driven by genome instability.
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Genome stability is central to human health. Genomic DNA in proliferating cells, however, is constantly subjected to stress due to the normal processes of cell growth. Homologous recombination (HR) can protect genomic DNA from such threats by providing high-fidelity DNA repair, but can conversely lead to genome instability when it is engaged improperly. Despite growing recognition of HR functions in the maintenance of genome stability, understanding of HR regulation remains a major challenge in the field. In this research programme, I aim to elucidate how HR, which is essentially catalysed by the Rad51 recombinase, is precisely regulated in proliferating cells. I will first elucidate the molecular mechanism underlying chromatin association of the tumour suppressor BRCA complex, which plays a primary role in recruiting Rad51 to sites of DNA damage, in proliferating cells. Secondly, I will investigate a pathway, initiated by phosphorylation of Rad51 by the Plk1 proto-oncogene product , that promotes Rad51 recruitment independently of the BRCA complex. We will identify factors that control this pathway using state-of-the-art proteomics methodology and will uncover their functions. Finally, I will map at high resolution the regions of DNA to which the HR proteins bind using deep sequencing technology combined with chromatin immunoprecipitation, in order to obtain a global view of their chromatin association and their roles in genome stability. The information obtained will advance our knowledge of HR regulation, and will provide a basis for the development of new strategies to treat human diseases associated with genome instability.
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