PhD Studentship: Novel genes required for checkpoint control and their role in colo arectal cancer

Background

Healthy aging is frequently affected by the onset of cancers. One in three of us will be affected over our lifetime, and 50% will have significantly reduced lifespan as a consequence. Cell cycle checkpoint genes are often mutated in cancers, while paradoxically, in appropriate circumstances, they may be attractive targets for rational drug design. Our laboratory was one of the first labs to identify the significance of the Chk1 gene product in checkpoint control and have a significant interest in novel therapeutics and their identification. Colorectal cancer remains a significant challenge, often due to late presentation of symptoms and Chk1 inhibitors are currently in clinical trials for a subset of colorectal cancers. Recently we have undertaken a genome-wide siRNA screen in colorectal cancer cells to identify previously unknown checkpoint pathway genes in order to identify novel potential therapeutic targets. As a result we have identified novel genes whose roles in checkpoint regulation are completely unknown.

Aims:

The aims of this project is to gain an understanding of the cellular function of one novel gene, which we have called MiCatS, in cellular checkpoint control. MiCatS-deficient cells appear to be unable to respond to cellular signalling pathways that indicate the presence of replication stress. This project will focus on developing an understanding of how MiCatS interferes with regulatory gene networks controlling genome integrity.

Techniques:

These will include a range of molecular cell biology techniques, tissue culture, confocal fluorescence microscopy, protein expression and functional characterisation approaches including proteomics, quantitative PCR, siRNA-mediated knockdown of gene expression, and immunoblotting.

References

(1) Feijoo, C., Hall-Jackson, C., Wu, R., Jenkins, D., Gilbert, D., and Smythe, C (2001). Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. The Journal of Cell Biology, 154(5), 913–924.
(2) Bowen, E., (2015). PhD Thesis. “A genomic screen for the identification of novel components of the S phase checkpoint”, University of Sheffield.
(3) https://www.sheffield.ac.uk/bms/research/csmythe#tab01