Toll-Like Receptors are activated by substances produced by microbial pathogens, such as lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria. This induces the formation of the Myddosome, a multi-protein complex, which recruits and activates at least three E3 ubiquitin ligases, termed TRAF6, Pellinos and LUBAC. These E3 ligases then generate hybrid ubiquitin chains containing both Lys63- and Met-1-ubiquitin linkages.
Parkinson’s disease is a leading cause of neurodegeneration. Despite decades of research, there are still no drugs available that can slow or halt disease progression. The discovery of rare gene mutations in patients with familial Parkinson’s has provided clues to the molecular basis of the disease however, the function of most genes is poorly understood. Our laboratory is interested in how mutations in the PTEN-induced kinase 1 (PINK1) lead to autosomal recessive Parkinson’s.
Recent advances from the Ciulli Lab and others have contributed to the establishment of a novel modality of chemical intervention into biological system – one that goes significantly beyond the state-of-the-art. Instead of blocking a target protein with conventional inhibitors, we are now designing and studying “tailored” molecules, bivalent conceptually and in function, that bring a protein target together with an E3 ubiquitin ligase (also known as PROTACs).
Gametes are formed by two successive rounds of cell division that occur after one round of chromosome replication. The first round (Meiosis I) separates the pairs of chromosomes, and the second (Meiosis II) separates the sister chromatids to produce the gametes, each of which has half the original amount of genetic information. Approximately 30% of human zygotes have abnormal chromosomal content at conception due to defects in meiosis. Such aneuploidy is a leading cause of miscarriages and other birth defects.
Advances in DNA sequencing technology have led to an explosion in available sequence data across many organisms. As a consequence, in human, exome and genome sequencing is now being used routinely to characterise the variability in the human population at the single base resolution in order to aid understanding of disease susceptibility. Large projects in the UK and internationally are in progress to sequence the complete genomes of tens of thousands of individuals with rare diseases and cancer while sequencing of cancer cell lines is revealing the complexity of evolution at the level of