Cancer cells that exhibit chromosome instability, or CIN, and harbour mutations in known CIN genes may be genetically “sensitized” to loss of function in other unlinked genes relative to normal cells that carry a wild-type copy of that CIN gene. By investigating genes that genetically interact with CIN genes, we may expose an “Achilles heel” that can be exploited by therapeutics to selectively kill only cancer cells carrying a CIN mutation. Ongoing work in the Hieter Lab using genome-wide synthetic lethal (SL) screens has yielded a large number of genes that genetically interact with CIN genes in yeast. These genes represent potential candidates whose human homologues may be SL with known cancer CIN genes. Recent work in the lab has already identified the human gene FEN1 to be SL with Rad54B- a known cancer gene. However, many more potential candidates from the growing list of CIN genetic interactions have not been investigated; nor has the application of using human genes for selective drug therapy been fully explored.
My research project probes candidate SL partner genes to better determine their potential as therapeutic targets. Initially, the project will focus on candidate partner genes involved in oxidative stress as these candidates interact with many important cancer CIN genes in genetic networks. Validation of the SL interaction between the candidate partner gene and the human CIN genes in mammalian cells will first determine if the interaction is conserved across species. If a negative interaction is observed, then the mechanism(s) of cell lethality and/or aneuploidy will be examined using biochemical and cell biology methods looking for alterations in protein activity, interactions, and localization. I also plan to screen for small molecule inhibitors of candidate partner genes. Use of these small molecule inhibitors in cells containing CIN mutations will validate whether the inhibitor represents a viable therapy for the selective killing of CIN-mutated cells.
Bailey M.L., Singh T., Mero P., Moffat J., and Hieter P. (2015) Dependence of Human Colorectal Cells Lacking the FBW7 Tumor Suppressor on the Spindle Assembly Checkpoint. Genetics 2015 Sep 8. [Epub ahead of print] Pubmed
Bailey M.L., O’Neil N.J., van Pel D.M., Solomon D.A., Waldman T., and Hieter P. (2014) Glioblastoma cells containing mutations in the cohesin component STAG2 are sensitive to PARP inhibition. Mol Cancer Ther 13(3):724-32. Pubmed
Sajesh B.V., Bailey M., Lichtensztejn Z., Hieter P., and McManus K.J. (2013) Synthetic lethal targeting of superoxide dismutase 1 selectively kills RAD54B-deficient colorectal cancer cells. Genetics 195(3):757-67. Pubmed
Bailey, M. L., Shilton, B. H., Brandl, C. J., and Litchfield, D. W. (2008) The dual histidine motif in the active site of Pin1 has a structural rather than catalytic role. Biochemistry 47, 11481-11489. Pubmed
Behrsin, C. D., Bailey, M. L., Bateman, K. S., Hamilton, K. S., Wahl, L. M., Brandl, C. J., Shilton, B. H., and Litchfield, D. W. (2007) Functionally important residues in the peptidyl-prolyl isomerase Pin1 revealed by unigenic evolution. J Mol Biol 365, 1143-1162. Pubmed