Mutations that cause chromosome instability (CIN) are considered important predisposing events that contribute to the initiation and/or progression of cancer. Our approach is to develop and apply genetic and biochemical methodologies to obtain an understanding of molecular components required for chromosome transmission, with the overarching goal of relating our work in yeast to human cancer.
The specific aims are: 1. To characterize essential CIN genes/pathways: shortened telomere CIN genes and the ASTRA complex. We will dissect the function of the ASTRA complex and its role in telomere biology and TORC1 signaling. 2. To characterize the roles of DNA damage and RNA processing in genome integrity. Five subunits of the mRNA cleavage and polyadenylation factor (CPF) exhibit CIN and high rates of spontaneous Rad52-foci while splicing factors show wild-type levels of damage. We will characterize the mechanism by which the CPF complex and other RNA processing factors cause DNA damage and/or CIN. 3. To validate candidate somatic mutations in CIN genes involved in telomere biology and RNA metabolism, and assess sensitization of cells to knockdown of candidate synthetic lethal partners. We will evaluate methods in yeast to determine whether specific mis-sense somatic mutations found in tumors are """"""""functional"""""""" and test synthetic lethal interactions predicted from yeast genetic interaction networks for evolutionary conservation in cultured mammalian cells. Further elucidation of the genetic basis of CIN in yeast will provide a mechanistic basis for understanding this process in human cells, and will provide candidate genes for those CIN genes mutated in cancer. Therefore, knowledge gained from this work will provide insight into tumorigensis. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

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Hieter, Philip A. PROJECT NARRATIVE We will be further defining the functions and mutational spectrum of genes that cause chromosome instability (CIN) in cancer using yeast as a model. By definition, mutations that cause CIN in cancer cells produce sub- lethal deficiencies in an essential cellular process (chromosome segregation) and therefore may represent a major untapped resource that could be exploited for therapeutic benefit in the treatment of cancer. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GGG-E (91))
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Pelroy, Richard
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University of British Columbia
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V6 1-Z3
Duffy, Supipi; Hieter, Philip (2018) The Chromosome Transmission Fidelity Assay for Measuring Chromosome Loss in Yeast. Methods Mol Biol 1672:11-19
Stirling, Peter C; Hieter, Philip (2017) Canonical DNA Repair Pathways Influence R-Loop-Driven Genome Instability. J Mol Biol 429:3132-3138
Duffy, Supipi; Fam, Hok Khim; Wang, Yi Kan et al. (2016) Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer. Proc Natl Acad Sci U S A 113:9967-76
Ang, J Sidney; Duffy, Supipi; Segovia, Romulo et al. (2016) Dosage Mutator Genes in Saccharomyces cerevisiae: A Novel Mutator Mode-of-Action of the Mph1 DNA Helicase. Genetics 204:975-986
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Bailey, Melanie L; Singh, Tejomayee; Mero, Patricia et al. (2015) Dependence of Human Colorectal Cells Lacking the FBW7 Tumor Suppressor on the Spindle Assembly Checkpoint. Genetics 201:885-95
Hamza, Akil; Tammpere, Erik; Kofoed, Megan et al. (2015) Complementation of Yeast Genes with Human Genes as an Experimental Platform for Functional Testing of Human Genetic Variants. Genetics 201:1263-74
Chan, Yujia A; Aristizabal, Maria J; Lu, Phoebe Y T et al. (2014) Genome-wide profiling of yeast DNA:RNA hybrid prone sites with DRIP-chip. PLoS Genet 10:e1004288
Price, Jessica C; Pollock, Lana M; Rudd, Meghan L et al. (2014) Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A. PLoS One 8:e63313
Stirling, Peter C; Shen, Yaoqing; Corbett, Richard et al. (2014) Genome destabilizing mutator alleles drive specific mutational trajectories in Saccharomyces cerevisiae. Genetics 196:403-12

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