In order to maintain genetic stability and prevent the amplification of chromosome segments, the process of DNA replication occurs in two strictly non-overlapping phases. In late mitosis and G1, replication origins are ‘licensed’ for replication by being loaded with double hexamers of MCM2-7 proteins. Then, during S phase, replication forks initiate at these licensed origins. Defects in regulation of the licensing system are associated with a variety of diseases including cancer and growth disorders .
We investigate the regulation and function of the mRNA cap, a modification of RNA essential for gene expression which integrates transcript processing and translation. We are beginning to understand how oncogenes and signalling pathways can regulate gene expression via regulation of mRNA capping enzymes. Signalling pathways which modify the mRNA capping enzymes have the potential to change the gene expression landscape, thus causing changes in cell physiology.
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.
To maintain their genetic integrity, eukaryotic cells must properly segregate their chromosomes to daughter cells during their cell division cycle. The unraveling of the mechanisms for chromosome segregation should improve our understanding of various human diseases such as cancers and congenital disorders, which are characterized by chromosome instability and aneuploidy. To study chromosome segregation, we use budding yeast and human cells as model systems. Overwhelming evidence suggests that the basic mechanisms of chromosome regulation are well conserved from yeast to humans.
The Findlay lab employs cutting-edge technologies to unravel Embryonic Stem (ES) cell signalling networks (Williams et al, Cell Rep 2016, Fernandez-Alonso et al, EMBO Rep 2017; Bustos et al, Cell Rep 2018), culminating in our recent discovery of the ERK5 pathway as an exciting new regulator of ES cell pluripotency. In order to uncover functions of ERK5 in ES cells, this project will deploy global proteomic and phosphoproteomic profiling. Novel ERK5 substrates and transcriptional networks will be characterised using biochemical and ES cell biology approaches.
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.
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.
Despite tremendous progress the origin of cancer is still a matter of debate for many malignancies, but it is clear that stem cells play an important part in this context. How are stem cells and the onset of tumorigenesis linked? Some stem cells can divide asymmetrically. This means that when they divide the stem cells self-renew and at the same time produce a daughter cell that will have another fate. If this process of cell fate assignment by asymmetric stem cell division goes wrong, tumourigenesis can be triggered.
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
Our bodies are home to trillions of bacteria and most of them reside in our guts. There is increasing evidence of links between our intestinal microbiota and inflammatory diseases including cardiovascular complaints, obesity, cancer and more directly, inflammatory bowel diseases. A single layer of epithelial cells forms the first line of defence in the gut and is the largest interface between microbes and our bodies. This layer of cells is interspersed with specialized immune cells known as Intraepithelial lymphocytes (IEL) that aid in its protection.