THE ART OF SCIENCE
is keeping an open mind
On this page you can find some example projects from the lab. However, if you would like a broader overview of the lab interests then please click here.
PP2A-B56 isoform specificity at kinetochores
At least three major mitotic processes are regulated by the PP2A-B56 phosphatase complex: the spindle assembly checkpoint (SAC), kinetochore-microtubule attachments and sister chromatid cohesion. We are investigating how these key functions of PP2A-B56, which require its localization to either the kinetochore or centromere are split between distinct subsets of B56 isoforms. PP2A-B56-gamma/delta localize to the outer kinetochore (via BUBR1) to regulate the SAC and chromosome alignment, whereas PP2A-B56-alpha/beta/epsilon localize to the centromere (via Sgo) to preserve cohesion. By using chimaeric B56 isoforms we have identified the mechanism for this differential localisation and we are now working to understand how this could be regulated during mitosis.
What insulates PP1 and PP2A-B56 from cross-talk at the kinetochore?
These two serine/threonine phosphatase complexes localise to an almost identical molecular space at kinetochores and yet they control different phosphorylation sites that are implicated in distinct processes. They show very little sequence specificity in vitro and therefore it is not clear what insulates these phosphatases from cross-talk. We have been using synthetic approaches to investigate this by switching their locations at the kinetochore. The results suggest that 1) geometric position is critical for phosphatase function, and 2) these phosphatase complexes have evolved separately to couple to different upstream inputs.
An interdisciplinary approach to interrogate the spindle assembly checkpoint network
The spindle assemble checkpoint (SAC) signal is regulated by two kinases (MPS1 and Aurora B) and two phosphatases (PP1 and PP2A-B56) at the kinetochore (read our paper on this here or a short article to explain here). We have now setup tools to visualise, quantify and manipulate all aspects of this network. This involves a combination of endogenous gene tagging (CRISPR/Cas9), quantitative microscopy (FRET, FRAP) and chemical genetics (to specifically relocalise phosphatase complexes with drugs). This is being combined with system biology - in collaboration with Andrea Ciliberto (Milan) and Andrew Goryachev (Edinburgh) - in an attempt to produce an in silico model that can predict in vivo behaviour. Preliminary predictions suggest this network may underlie a robust SAC signal.
A computer game to inform about the progression and evolution of cancer
Cancer is a progressive disease that results from mutations that accrue in different tissues throughout life. These mutations are for cancer what narrowing arteries are for heart disease: both underlie their respective diseases and both progress throughout life at different rates depending on risk factors. The problem is that most people see cancer as an all or nothing disease, which makes them less likely to take lifestyle choice in early life to help prevent it. Also, it is easy to visualise what a bacon roll may do for a narrowing artery, but not many people understand what smoking actually does to our cells.
We are currently developing an computer game - in collaboration with Robin Sloan (Abertay University) - to inform teenagers about the genesis, evolution and progression of cancer. The player tries to control the spread of mutant cells in a strategic game, and in doing so, experiences exactly why the mutational burden from risk factors is so bad.
Play the latest game here