Molecular biology of eukaryotic chromosome transmission, cancer therapeutics, model organism and human disease.
Changes in genome structure and sequence underlie tumorigenesis; genes that maintain genome structure are often somatically mutated in cancer and are evolutionarily conserved. Thus, mutations that cause genome instability are considered important predisposing events that contribute to the initiation and/or progression of cancer. Our general approach is to develop and apply genetic and biochemical methodologies in the model organism, Saccharomyces cerevisiae (bakers yeast), to obtain an understanding of molecular components required for chromosome transmission, with the overarching goal of relating our work in yeast to human cancer. We have established an extensive genome instability gene catalog in yeast that provides a resource to identify cross species, candidate human genes that are somatically mutated and could cause chromosome instability (CIN) in cancer. Our functional studies of selected CIN genes in yeast have elucidated mechanistic insights into various aspects of the chromosome cycle, including sister chromatid cohesion, kinetochores, DNA replication and repair, and cell cycle checkpoints. We have also developed a strategy to identify genes in yeast synthetic lethal (SL) interaction networks as a means for identifying novel cancer drug targets. By definition, mutations that cause CIN in cancer cells produce “sub-lethal” deficiencies in an essential cellular process (chromosome maintenance) and therefore may represent genetic vulnerabilities in tumor cells that could be exploited for therapeutic benefit in the treatment of cancer. To identify candidate drug targets, we have been testing synthetic lethal interactions, predicted in yeast, using RNAi, gene knockouts, and mutants in both C. elegans and mammalian cell culture, to identify evolutionarily conserved SL gene pairs involving CIN genes somatically mutated in cancer. Our research involves a direct path from identification and mechanistic studies of CIN genes in yeast, to mining sequence data for orthologs mutated in cancer, to interrogation of the function of somatic variants and finally the identification of (1) therapeutic target genes defined by synthetic lethality and (2) small-molecule inhibitors of those targets.
Recent selected publications:
O’Neil NJ, Bailey ML, Hieter P. (2017). Synthetic lethality and cancer. Nat Rev Genet. Oct;18(10):613-623. doi: 10.1038/nrg.2017.47.
Xu H, Di Antonio M, McKinney S, Mathew V, Ho B, O’Neil NJ, Santos ND, Silvester J, Wei V, Garcia J, Kabeer F, Lai D, Soriano P, Banáth J, Chiu DS, Yap D, Le DD, Ye FB, Zhang A, Thu K, Soong J, Lin SC, Tsai AH, Osako T, Algara T, Saunders DN, Wong J, Xian J, Bally MB, Brenton JD, Brown GW, Shah SP, Cescon D, Mak TW, Caldas C, Stirling PC, Hieter P, Balasubramanian S, Aparicio S. (2017). CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun. 2017 Feb 17;8:14432. doi: 10.1038/ncomms14432.
Boycott KM, Rath A, Chong JX, Hartley T, Alkuraya FS, Baynam G, Brookes AJ, Brudno M, Carracedo A, den Dunnen JT, Dyke SOM, Estivill X, Goldblatt J, Gonthier C, Groft SC, Gut I, Hamosh A, Hieter P, et al. (2017). Internatioanal cooperation to enable the diagnosis of all rare genetic diseases. Am J Hum Genet. May 4;100(5):695-705. doi: 10.1016/j.ajhg.2017.04.003.
Wangler MF, Yamamoto S, Chao HT, Posey JE, Westerfield M, Postlethwait J; Members of the Undiagnosed Diseases Network (UDN), Hieter P, Boycott KM, Campeau PM, Bellen HJ. (2017). Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research. Genetics. 2017 Sep;207(1):9-27. doi: 10.1534/genetics.117.203067.
Stirling, P., Hieter, P. (2016). Canonical DNA repair pathways influence R-loop driven genome instability. J. Mol. Biol. pii: S0022-2836(16)30259-5. doi: 10.1016/j.jmb.2016.07.014.
Ang, J.S., Duffy, S., Segovia, R., Stirling, P., Hieter, P. (2016). Dosage mutator genes in S. cerevisiae: A novel mutator mode-of-action of the Mph1 DNA helicase. Genetics 204(3):975-986. doi: 10.1534/genetics.116.192211.
Duffy, S., Fam, H.K., Wang, Y., Styles, E., Kim, J-H., Ang, J.S., Singh, T., Larionov, V., Shah, S., Andrews, B., Boerkoel, C., Hieter, P. (2016). Over-expression screens identify conserved dosage chromosome instability genes in yeast and human cancer. Proc. Natl. Acad. Sci. USA 113:9967-76. doi: 10.1073/pnas.1611839113.
Kofoed, M., Milbury, K.L., Chiang, J.H., Sinha, S., Ben-Aroya, S., Giaever, G., Nislow, C., Hieter, P., Stirling, P.C. (2015). An updated collection of sequence barcoded temperature-sensitive alleles of yeast essential genes. G3: Genes Genomes Genetics 5(9):1879-87.
Bailey, M.L., Singh, T., Mero, P., Moffat, J., Hieter, P. (2015). Dependence of human colorectal cells lacking the FBW7 tumor suppressor on the spindle assembly checkpoint. Genetics, 201:885-95. doi:101534/genetics.115.180653.
Hamza, A., Tammpere, E., Kofoed, M., Keong, C., Chiang, J., Giaever, G., Nislow, C., Hieter, P. (2015). Complementation of yeast genes with human genes as an experimental platform for functional testing of human genetic variants. Genetics 201: 1263-74. doi:10.1534/genetics.115.18109.
Li, X., O’Neil, N.J., Moshgabadi, N., Hieter, P. (2014) Synthetic Cytotoxicity: Digenic Interactions with TEL1/ATM Mutations Reveal Sensitivity to Low Doses of Camptothecin. Genetics 197(2):611-23.
Chan, Y.A., Aristizabal, M.J., Lu, P.Y., Luo, Z., Hamza, A., Kobor, M.S., Stirling, P.C., Hieter, P. (2014). Genome-wide profiling of yeast DNA: RNA hybrid prone sites with DRIP-chip. PLoS Genet 10(4):e1004288.
Chan, Y.A., Hieter, P., Stirling, P.C. (2014). Mechanisms of genome instability induced by RNA-processing defects. Trends in Genetics 30(6):245-53.
Hieter, P., Boycott, K. (2014). Understanding rare disease pathogenesis: A grand challenge for model organisms. Genetics 198(2):443-5.
Bailey, M.L., O’Neil, N.J., van Pel, D.M., Solomon, D.A., Waldman, T., Hieter, P. (2014). Glioblastoma cells containing mutations in the cohesion component, STAG2, are sensitive to PARP inhibition. Mol Cancer Ther 13(3):724-32.