Kevin gives a brief overview of his research.
During mitosis cells must segregate the replicated copies of their genome to their daughter cells with extremely high fidelity. Segregation errors lead to an abnormal chromosome number (aneuploidy), which typically results in disease or death. A number of mechanisms are employed by cells to ensure that mitosis is error-free, and one of the most important of these is the spindle checkpoint. This checkpoint acts as a mitotic surveillance system, and monitors the interaction between chromosomes and the mitotic spindle. Only when all chromosomes are attached to spindle microtubules in a bi-polar manner, with each pair of sister-chromatids attached to opposite spindle poles, is anaphase allowed to proceed. Through our studies we aim to understand what checkpoint components sense at kinetochores (is it simply lack of attachment or also lack of tension?), and how the checkpoint (Mad and Bub) proteins act to inhibit Cdc20-APC/C activity and thereby delay the onset of anaphase.
The Mad and Bub proteins are essential in vertebrates: in their absence every mitosis is too short and massive chromosome segregation errors occur, leading to apoptosis. Abnormal expression, or mutation, of Mad and Bub proteins can give rise to aneuploidy and are implicated in cancer progression.
We employ fission yeast as a model systems in our studies of mitosis and spindle checkpoint mechanism. The Schizosaccharomyces pombe spindle checkpoint is not essential, making it far simpler to study. Amongst other exciting projects, we currently work on:
a) structure-function analysis of the Mad and Bub proteins.
b) identification of the key substrates of the Mps1, Bub1 and Aurora kinases.
c) identification and analysis of checkpoint silencing mechanisms. How does protein phosphatase (PP1) activity aid anaphase onset once the checkpoint is satisfied? What other mechanisms are involved in turning off / silencing checkpoint signals? Genome-wide genetic screens and proteomic studies are underway to identify further silencing factors.
d) developing synthetic biology approaches to induce and regulate artificial checkpoint arrest in cells. See http://dx.doi.org/10.1016/j.cub.2016.11.014
e) analysing the spindle checkpoint in Cryptococcus neoformans, and studying the consequences of prolonged mitotic arrest in this fungal pathogen.