The aim of my research is to gain a deeper understanding of the genetic networks that affect the development and progression of human cancer tumours in order to identify targets for new anti-tumour therapeutics. The principle underlying my research approach is that many mechanisms and pathways involved in chromosome stability and proliferation control are evolutionarily conserved across organisms.
Cancer arises from a series of alterations in a defined set of biological processes. Tumours exhibit characteristic phenotypes including: genomic instability, cell cycle dysfunction, loss of growth factor signal control, immortalization, metastasis/invasion, and apoptotic checkpoint failure. Although most malignant tumours display all or most of these traits, the specific gene mutations that give rise to these traits can vary greatly between tumours resulting in significant genetic diversity. Such genetic diversity requires a systematic approach to unravel the biological consequences of the genetic changes responsible for tumour development. Simple animal models provide an effective and efficient experimental tool with which to investigate the function and biological relevance of mutations identified in human cancer tumours. I am using the nematode Caenorhabditis elegans as a platform to investigate the complex molecular genetic networks associated with genomic instability and cancer.
Most of the pathways implicated in cancer are highly conserved between humans and C. elegans. C. elegans has orthologues of many genes associated with cancer including p53, retinoblastoma (Rb), Ras, BRCA1, BRCA2, BLM, FANCD2 and FANCJ. Research over the past decade has shown that loss of function of cancer-associated genes in C. elegans result in informative phenotypes that are analogous to those observed in human tumours: increased mutation rate, chromosome instability, checkpoint dysfunction, cell cycle defects, telomere length variation and hyperplasia. In C. elegans, informative phenotypes coupled with high-throughput loss and gain of function assays make it possible to study the network of cancer-associated genes in a whole live organism. In many ways, C. elegans is an animal model that combines the technical advantages of a single celled organism, such as yeast, with a gene complement more akin to human. My research project is developing a genetic interaction network of cancer-associated genes and DNA damage response genes in Caenorhabditis elegans. Genetic interactions uncovered in C. elegans are then prioritized for testing in cultured cancer cells with the aim of identifying potential chemotherapeutic targets.
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: 611-623. *These authors contributed equally to this work.
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 cohesin component, STAG2, are sensitive to PARP inhibition. Molecular Cancer Therapeutics. 13(3): 724-732.
O’Neil N.J., Youds J.L., Ward J., Petalcorin M., Martin J., Rose A.M., Boulton S.J. (2013). The Mus81 and XPF endonucleases function redundantly to process meiotic recombination intermediates in C. elegans. PLoS Genetics. 9(7): e1003582.
O’Neil N.J., van Pel D.M., Hieter P. (2013). Synthetic Lethality and Cancer: Cohesin and PARP at the Replication Fork.
Trends in Genetics. 29(5): 290-7.
Le Gallo M., O’Hara A.J., Rudd M., O’Neil N.J., Urick M.E., Price J.C., England B.M., Zhang S., Godwin A.K., Sgroi D.C., Hansen N.F., The NIH Intramural Sequencing Center, Mullikin J., Merino M.J., Hieter P., Bell D.W. (2012). Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes.
Nature Genetics. 44(12): 1310-5.
McLellan J.*, O’Neil N.J.*, Barrett I., Ferree E., Van Pel D., Ushey K., Sipahimalani P., Bryan J., Rose A.M., Hieter P. (2012). Synthetic Lethality of Cohesins with PARPs and Replication Fork Mediators. PLoS Genetics. 8(3): e1002574. *These authors contributed equally to this work.
Chung G., O’Neil N.J., Rose A.M. (2011). Loss of CHL-1 affects cell proliferation and chromosome stability in Caenorhabditis elegans. DNA Repair. 10: 1174-82.
Youds, J.L., Mets, D.G., McIlwraith, M.J., Martin, J.S., Ward, J.D., O’Neil, N.J., Rose, A.M., West, S.C., Meyer, B.J., Boulton, S.J. (2010). RTEL-1 enforces meiotic crossover interference and homeostasis. Science. 327: 1254-8.
Rose, A.M., O’Neil, N.J., Bilenky, M., Butterfield, Y.S., Malhis, N., Flibotte, S., Jones, M.R., Marra, M., Baillie, D.L., Jones, S.J. (2010). Genomic sequence of a mutant strain of Caenorhabditis elegans with an altered recombination pattern. BMC Genomics. 11: 131.
McLellan, J., O’Neil, N.J., Tarailo, S., Stoepel, J., Bryan, J., Rose, A.M., Hieter, P. (2009). Synthetic lethal genetic interactions that decrease somatic cell proliferation in Caenorhabditis elegans identify the alternative RFC CTF18 as a candidate cancer drug target. Molecular Biology of the Cell. 20: 5306-13.
Jones M.R., Chua, S.Y., O’Neil, N.J., Johnsen, R.C., Rose, A.M., Baillie, D.L. (2009). High Resolution CGH Analysis reveals unanticipated complexity of genetic deficiencies on chromosome V in Caenorhabditis elegans. Molecular Genetics and Genomics. 282: 37-46.
Barber, L., Youds, J.L., Ward, J., McIlwraith, M., O’Neil, N.J., Petalcorin, M., Martin, S., Collis, S., Cantor, S., Auclair, M., Tissenbaum, H., West, S.C., Rose, A.M., Boulton, S.J. (2008). RTEL1 maintains genomic stability by suppressing homologous recombination. Cell. 135: 261-71.
Zhao, Y., Tarailo-Graovac, M., O’Neil, N.J., Rose, A.M. (2008). Spectrum of mutational events in the absence of DOG-1/FANCJ in Caenorhabditis elegans. DNA Repair. 7: 1846-54.
Youds, J.L., Barber, L., Ward, J.D., Collis, S., O’Neil, N.J., Boulton, S.J., Rose, A.M. (2008). DOG-1 is the Caenorhabditis elegans BRIP1/FANCJ homologue and functions in interstrand cross-link repair. Molecular and Cellular Biology 28:1470-9.
Astin, J.W., O’Neil, N.J., Kuwabara, P.E. (2008). Nucleotide excision repair and the degradation of RNA pol II by the Caenorhabditis elegans XPA and Rsp5 orthologues, RAD-3 and WWP-1. DNA Repair. 7: 267-80.
Zhao, Y., O’Neil, N.J., Rose, A.M. (2007). Poly-G/poly-C tracts in the genomes of Caenorhabditis. BMC Genomics 8: 403.
Huang, P., Pleasance, E., Maydan, J., Newbury, R., O’Neil, N.J., Baillie, D.L., Marra, M., Moerman, D., Jones, S.J. (2007). Identification and analysis of internal promoters in Caenorhabditis elegans operons. Genome Research. 17: 1478-85.