title: Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer.
abstract: Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1 Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
authors.forename: Supipi
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;
authors.forename: Hok Khim
authors.initials: HK
authors.lastname: Fam
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada V5Z 4E6;
authors.forename: Yi Kan
authors.initials: YK
authors.lastname: Wang
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1;
authors.forename: Erin B
authors.initials: EB
authors.lastname: Styles
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
authors.forename: J Sidney
authors.initials: JS
authors.lastname: Ang
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
authors.forename: Tejomayee
authors.initials: T
authors.lastname: Singh
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Larionov
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada V5Z 4E6;
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1;
authors.forename: Brenda
authors.initials: B
authors.lastname: Andrews
authors.affiliation: Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z3; hieter@msl.ubc.ca.
authors.forename: Philip
authors.initials: P
authors.lastname: Hieter
mesh_terms: D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D056464:Histone Deacetylase 2 / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics*; D014635:Valproic Acid / Q000008:administration & dosage
chemical_list: D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D029701:Saccharomyces cerevisiae Proteins; C470012:TAF12 protein, human; D035381:TATA-Binding Protein Associated Factors; C012589:trichostatin A; D014635:Valproic Acid; D010727:Phosphoric Diester Hydrolases; C505435:Tdp1 protein, S cerevisiae; C071665:RPD3 protein, S cerevisiae; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases
keywords: TDP1; dosage chromosome instability; overexpression; rhabdomyosarcoma; synthetic dosage lethality