Research Interests
Each day, a human cell experiences tens of thousands of DNA lesions resulting from a variety of chemical, mechanical and radiation sources. Unless this damage is repaired, mutations arise that can lead to a variety of diseases, but particularly cancer, so elegant systems have evolved to carry out the repair process. There are two main research projects in the lab:
Modification of chromatin in response to DNA damage
Although the regulation of chromatin is complex and diverse, three major aspects are:
- Nucleosome remodelling
- Covalent modifications (including phosphorylation, acetylation, ubiquitylation)
- Histone exchange.
All of these processes are involved in the DNA damage response which not only provides a general model for understanding many aspects of chromatin dynamics but also has implications for diseases such as cancer and a number of neurodegenerative disorders (including Alzheimer’s, Huntington’s and Parkinson’s diseases) that appear to have a link with accumulated DNA damage and/or defective DNA repair. We aim to understand the structure and mechanism of a number of different multi-subunit complexes that regulate chromatin.
This project is funded by a Wellcome Senior Investigator Award.
Repair of DNA double-strand breaks
The aims of this project are to understand the structure and mechanism of the processing of double-strand DNA breaks as a prelude to recombination repair. Defects in this process cause problems with the repair of DNA damage leading to genomic instability that results in cancer. Ongoing work on the RecBCD/AddAB systems have revealed insights into this process in bacteria. and recent work has revealed the similarity between the process in bacteria and humans even though the proteins are not conserved. The first aspect of these studies on the tractable, but nontheless complex, bacterial systems.
The second aspect of the proposal is to extend what we have learned from RecBCD/AddAB to the human double-strand break repair system which is even more complex and presents some challenging problems in structural biology. However, meeting these challenges is essential if we are to understand fully how these multi-component systems cooperate to repair DNA damage, and hence prevent cancer, in humans.
This project is funded by a Cancer Research UK Programme grant.
