title: Leveraging DNA damage response signaling to identify yeast genes controlling genome stability.
abstract: Oncogenesis frequently is accompanied by rampant genome instability, which fuels genetic heterogeneity and resistance to targeted cancer therapy. We have developed an approach that allows precise, quantitative measurement of genome instability in high-throughput format in the Saccharomyces cerevisiae model system. Our approach takes advantage of the strongly DNA damage-inducible gene RNR3, in conjunction with the reporter synthetic genetic array methodology, to infer mutants exhibiting genome instability by assaying for increased Rnr3 abundance. We screen for genome instability across a set of ~1000 essential and ~4200 nonessential mutant yeast alleles in untreated conditions and in the presence of the DNA-damaging agent methylmethane sulfonate. Our results provide broad insights into the cellular processes and pathways required for genome maintenance. Through comparison with existing genome instability screens, we isolated 130 genes that had not previously been linked to genome maintenance, 51% of which have human homologs. Several of these homologs are associated with a genome instability phenotype in human cells or are causally mutated in cancer. A comprehensive understanding of the processes required to prevent genome instability will facilitate a better understanding of its sources in oncogenesis.
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hendry
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Guihong
authors.initials: G
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jiongwen
authors.initials: J
authors.lastname: Ou
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada Donnelly Centre, University of Toronto, Toronto, Ontario, Canada grant.brown@utoronto.ca.
authors.forename: Grant W
authors.identifier: http://orcid.org/0000-0002-9002-5003
authors.initials: GW
authors.lastname: Brown
mesh_terms: D004249:DNA Damage; D019143:Evolution, Molecular; D015966:Gene Expression Regulation, Fungal; D063990:Gene Ontology; D005800:Genes, Fungal; D042822:Genomic Instability; D023281:Genomics; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015003:Yeasts / Q000235:genetics* / Q000378:metabolism*
keywords: DNA damage; DNA repair; DNA replication; genome instability; ribonucleotide reductase