Molecular biology of eukaryotic chromosome transmission, cancer therapeutics, model organism and human disease.
Changes in genome structure and sequence underlie tumorigensis. Genes that maintain genome structure are evolutionarily conserved and are often somatically mutated in cancer. 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, CRISPR-Cas9 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.
Ye FB, Hamza A, Singh T, Flibotte S, Hieter P, O’Neil NJ. (2020). A Multimodal Genotoxic Anticancer Drug Characterized by Pharmacogenetic Analysis in Caenorhabditis elegans. Genetics. 2020 Jul;215(3):609-621. doi: 10.1534/genetics.120.303169.
Boycott KM, Campeau PM, Howley HE, Pavlidis P, Rogic S, Oriel C, Berman JN, Hamilton RM, Hicks GG, Lipshitz HD, Masson JY, Shoubridge EA, Junker A, Leroux MR, McMaster CR, Michaud JL, Turvey SE, Dyment D, Innes AM, van Karnebeek CD, Lehman A, Cohn RD, MacDonald IM, Rachubinski RA, Frosk P, Vandersteen A, Wozniak RW, Pena IA, Wen XY, Lacaze-Masmonteil T, Rankin C, Hieter P. (2020). The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms. Am J Hum Genet. Feb 6;106(2):143-152. doi: 10.1016/j.ajhg.2020.01.009.
The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms. Am J Hum Genet. Feb 6;106(2):143-152. doi: 10.1016/j.ajhg.2020.01.009.
Hamza A, Driessen MRM, Tammpere E, O’Neil NJ, Hieter P. (2020). Cross-Species Complementation of Nonessential Yeast Genes Establishes Platforms for Testing Inhibitors of Human Proteins. Genetics. Mar;214(3):735-747. doi: 10.1534/genetics.119.302971.
Chang EY, Tsai S, Aristizabal MJ, Wells JP, Coulombe Y, Busatto FF, Chan YA, Kumar A, Dan Zhu Y, Wang AY, Fournier LA, Hieter P, Kobor MS, Masson JY, Stirling PC. (2019). MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription-replication conflicts. Nat Commun. 2019 Sep 19;10(1):4265. doi: 10.1038/s41467-019-12271-w.
Tyson JR, O’Neil NJ, Jain M, Olsen HE, Hieter P, Snutch TP. (2018). MinION-based long-read sequencing and assembly extends the C. elegans reference genome. Genome Res. Feb;28(2):266-274. doi: 10.1101/gr.221184.117. Epub 2017 Dec 22. PMID:29273626
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.