The Genome Integrity and Neurodegeneration group is studying the structural biology of human disease, with a loose focus on two areas: DNA damage recognition and repair, and the impact of genetic variation on human disease.
Our DNA is continuously exposed to chemical damage, both from extraneous mutagens and from products of our own oxidative metabolism. Furthermore, the process of DNA replication in dividing cells involves intermediates such as replication forks, which have the potential to degenerate into breaks in the DNA. Most types of DNA damage are detrimental to cell survival, and all cells have highly complex mechanism of detecting and repairing DNA damage, and arresting cell division until such damage is repaired. We are investigating several classes of DNA repair proteins, primarily DNA helicases (pictured), nucleases, and polymerases. Our aim is to use structural analysis to understand the underlying mechanisms. In parallel, we are searching for small molecules that could modulate DNA repair pathways, hoping to selectively kill cancer cells based on their inherent genomic instability.
Genome-wide association studies (GWAS), sequencing of cancer genomes, and systematic expression analyses are generating a growing list of suggested links between genes and diseases. While the statistical robustness of these studies is continuously improving, a substantial fraction of the genes discovered have little-known functions or relation to diseases. To elucidate these functions and their implications, we will produce proteins involved in inflammatory and neurological diseases. The purified proteins will be used to derive structures, antibodies and activity assays.
Joseph graduated from Edinburgh University where he studied for a bachelor’s degree in Biochemistry. He then moved to study a PhD in the Department of Molecular Biology and Biochemistry at the University of Sheffield, where he studied the structure-function relationships of essential gene products in the Gram positive model organism, Bacillus subtilis using X-ray crystallography. He continued to work on proteins of functional importance to B. subtilis when he joined the group of Professor Richard Lewis at the Institute for Cell and Molecular Biosciences at the University of Newcastle in 2007 where his work focussed on the structural and functional characterization of proteins involved in RNA processing and degradation. Joseph joined the SGC Genome Integrity group in February 2013 and his current research interests include helicases and nucleic acid translocases, and DNA repair pathways.