The DNA Damage Response (DDR) is a major component of a cells defence against disease. It serves to recognize and repair DNA damage, to regulate cell-cycle progression and where necessary, promote programmed cell death. One of the most potentially dangerous forms of DNA damage is a double stranded DNA break (DSB), which must be dealt with to maintain the structural and genetic integrity of a cell. Failure to do so results in generation of chromosomal aberrations such as chromosomal translocations that are potentially tumorigenic.
DSB are not homogeneous. They can occur in various forms depending on how they are generated and may be one-ended or two-ended, may have blunt or ragged termini or may even form hairpins. Moreover they can arise in different parts of the cell cycle where the opportunities for repair are different.
Generally DSB are repaired by either simple, but often inaccurate non-homologous end-joining pathway, or by more complex, but also more accurate, homologous recombination. How cells ‘decide’ which pathway is used to repair different DSB is unclear, but has important implications for understanding how cancer promoting chromosomal translocations are generated and how DNA damage can be used as a therapeutic agent. A key component in this decision is the tumor suppressor protein BRCA1.
This project will investigate how recruitment of BRCA1 and its associated factors to sites of DNA damage regulates the different pathways for repair of DNA breaks. We have recently found that nuclear shuttling of specific DNA repair factors can impact on the regulation of DSB repair. We will investigate the structural and functional interactions made by these factors and design a screen for small molecules that might enable us to chemically regulate DNA repair for therapeutic purposes.
The project will involve biochemical and possibly structural analysis of proteins, genetic investigation of protein function and cell biological methods for visualization of DNA repair in cells. Screening for small molecules will be performed in collaboration with the Dundee Drug Discovery Unit.
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