title: Dissection of DNA damage responses using multiconditional genetic interaction maps.
abstract: To protect the genome, cells have evolved a diverse set of pathways designed to sense, signal, and repair multiple types of DNA damage. To assess the degree of coordination and crosstalk among these pathways, we systematically mapped changes in the cell's genetic network across a panel of different DNA-damaging agents, resulting in ~1,800,000 differential measurements. Each agent was associated with a distinct interaction pattern, which, unlike single-mutant phenotypes or gene expression data, has high statistical power to pinpoint the specific repair mechanisms at work. The agent-specific networks revealed roles for the histone acetyltranferase Rtt109 in the mutagenic bypass of DNA lesions and the neddylation machinery in cell-cycle regulation and genome stability, while the network induced by multiple agents implicates Irc21, an uncharacterized protein, in checkpoint control and DNA repair. Our multiconditional genetic interaction map provides a unique resource that identifies agent-specific and general DNA damage response pathways.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
authors.forename: Aude
authors.initials: A
authors.lastname: Guénolé
authors.forename: Rohith
authors.initials: R
authors.lastname: Srivas
authors.forename: Kees
authors.initials: K
authors.lastname: Vreeken
authors.forename: Ze Zhong
authors.initials: ZZ
authors.lastname: Wang
authors.forename: Shuyi
authors.initials: S
authors.lastname: Wang
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.forename: Haico
authors.initials: H
authors.lastname: van Attikum
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D016681:Genome, Fungal; D042822:Genomic Instability; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C501395:RAD17 protein, S cerevisiae; C107849:SAE2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D051548:Histone Acetyltransferases; C517120:Rtt109 protein, S cerevisiae; D004720:Endonucleases; C502440:PPH3 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases