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PMID: 16121259 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Genome-wide requirements for resistance to functionally distinct DNA-damaging agents.

PLoS genetics ·Vol. 1 ·No. 2 ·2005-08-00 ·Pages e24

Lee W, St Onge RP, Proctor M, Flaherty P, Jordan MI, Arkin AP, Davis RW, Nislow C, Giaever G

Abstract

The mechanistic and therapeutic differences in the cellular response to DNA-damaging compounds are not completely understood, despite intense study. To expand our knowledge of DNA damage, we assayed the effects of 12 closely related DNA-damaging agents on the complete pool of approximately 4,700 barcoded homozygous deletion strains of Saccharomyces cerevisiae. In our protocol, deletion strains are pooled together and grown competitively in the presence of compound. Relative strain sensitivity is determined by hybridization of PCR-amplified barcodes to an oligonucleotide array carrying the barcode complements. These screens identified genes in well-characterized DNA-damage-response pathways as well as genes whose role in the DNA-damage response had not been previously established. High-throughput individual growth analysis was used to independently confirm microarray results. Each compound produced a unique genome-wide profile. Analysis of these data allowed us to determine the relative importance of DNA-repair modules for resistance to each of the 12 profiled compounds. Clustering the data for 12 distinct compounds uncovered both known and novel functional interactions that comprise the DNA-damage response and allowed us to define the genetic determinants required for repair of interstrand cross-links. Further genetic analysis allowed determination of epistasis for one of these functional groups.

MeSH Terms
Antifungal Agents/pharmacology Cluster Analysis DNA Damage/drug effects,genetics DNA Repair/genetics Drug Resistance/genetics Epistasis, Genetic Genome, Fungal Saccharomyces cerevisiae/genetics Sequence Deletion
Chemicals
Antifungal Agents
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Lee William
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
St Onge Robert P
Proctor Michael
Flaherty Patrick
Jordan Michael I
Arkin Adam P
Davis Ronald W
Nislow Corey
Giaever Guri
Conflict of Interest

Competing interests. The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7390
DOI
10.1371/journal.pgen.0010024
Published
2005-08-00
Epub
2005-00-19
Pages
e24
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC1189734
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pgen.0010024 PMC Full Text
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