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PMID: 17206143 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions.

Nature genetics ·Vol. 39 ·No. 2 ·2007-02-00 ·Pages 199-206

St Onge RP, Mani R, Oh J, Proctor M, Fung E, Davis RW, Nislow C, Roth FP, Giaever G

Abstract

Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination-derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order.

MeSH Terms
DEAD-box RNA Helicases/genetics DNA Repair Gene Deletion Genes, Fungal Methyl Methanesulfonate/toxicity Models, Genetic Molecular Sequence Data RecQ Helicases/genetics Recombination, Genetic Saccharomyces cerevisiae/genetics Saccharomyces cerevisiae Proteins/genetics
Chemicals
Saccharomyces cerevisiae Proteins Methyl Methanesulfonate MPH1 protein, S cerevisiae SGS1 protein, S cerevisiae RecQ Helicases DEAD-box RNA Helicases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
St Onge Robert P
Department of Biochemistry, Stanford University, Stanford, California 94305, USA.
Mani Ramamurthy
Oh Julia
Proctor Michael
Fung Eula
Davis Ronald W
Nislow Corey
Roth Frederick P
Giaever Guri
References (45)
45 references, click to expand
  1. Principles for the buffering of genetic variation.
    Science. 2001 Feb 9;291(5506):1001-4 PMID: 11232561
  2. Commensurate distances and similar motifs in genetic congruence and protein interaction networks in yeast.
    BMC Bioinformatics. 2005;6:270 PMID: 16283923
  3. Ordering gene function: the interpretation of epistasis in regulatory hierarchies.
    Trends Genet. 1992 Sep;8(9):312-6 PMID: 1365397
  4. Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins.
    Cell. 2004 Sep 17;118(6):699-713 PMID: 15369670
  5. Modular epistasis in yeast metabolism.
    Nat Genet. 2005 Jan;37(1):77-83 PMID: 15592468
  6. Break-induced replication and recombinational telomere elongation in yeast.
    Annu Rev Biochem. 2006;75:111-35 PMID: 16756487
  7. Cloning-free PCR-based allele replacement methods.
    Genome Res. 1997 Dec;7(12):1174-83 PMID: 9414323
  8. A comprehensive two-hybrid analysis to explore the yeast protein interactome.
    Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4569-74 PMID: 11283351
  9. Systematic genetic analysis with ordered arrays of yeast deletion mutants.
    Science. 2001 Dec 14;294(5550):2364-8 PMID: 11743205
  10. Saccharomyces cerevisiae MPH1 gene, required for homologous recombination-mediated mutation avoidance, encodes a 3' to 5' DNA helicase.
    J Biol Chem. 2005 Mar 4;280(9):7854-60 PMID: 15634678
  11. Rad51-dependent DNA structures accumulate at damaged replication forks in sgs1 mutants defective in the yeast ortholog of BLM RecQ helicase.
    Genes Dev. 2005 Feb 1;19(3):339-50 PMID: 15687257
  12. Combining biological networks to predict genetic interactions.
    Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15682-7 PMID: 15496468
  13. A genetic screen for top3 suppressors in Saccharomyces cerevisiae identifies SHU1, SHU2, PSY3 and CSM2: four genes involved in error-free DNA repair.
    Genetics. 2005 Mar;169(3):1275-89 PMID: 15654096
  14. Global synthetic-lethality analysis and yeast functional profiling.
    Trends Genet. 2006 Jan;22(1):56-63 PMID: 16309778
  15. The Bloom's syndrome gene product is homologous to RecQ helicases.
    Cell. 1995 Nov 17;83(4):655-66 PMID: 7585968
  16. A Rad52 homolog is required for RAD51-independent mitotic recombination in Saccharomyces cerevisiae.
    Genes Dev. 1996 Aug 15;10(16):2025-37 PMID: 8769646
  17. The language of gene interaction.
    Genetics. 1998 Jul;149(3):1167-71 PMID: 9649511
  18. Simulation of quantitative characters from qualitatively acting genes : I. Nonallelic gene interactions involving two or three loci.
    Theor Appl Genet. 1971 Jan;41(5):216-26 PMID: 24430247
  19. A DNA integrity network in the yeast Saccharomyces cerevisiae.
    Cell. 2006 Mar 10;124(5):1069-81 PMID: 16487579
  20. A strategy for extracting and analyzing large-scale quantitative epistatic interaction data.
    Genome Biol. 2006;7(7):R63 PMID: 16859555
  21. Global mapping of the yeast genetic interaction network.
    Science. 2004 Feb 6;303(5659):808-13 PMID: 14764870
  22. Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation of toxic recombination intermediates from single-stranded gaps created by DNA replication.
    Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16887-92 PMID: 12475932
  23. Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair.
    EMBO J. 2000 Jul 3;19(13):3388-97 PMID: 10880451
  24. Yeast Rad55 and Rad57 proteins form a heterodimer that functions with replication protein A to promote DNA strand exchange by Rad51 recombinase.
    Genes Dev. 1997 May 1;11(9):1111-21 PMID: 9159392
  25. Derivation of genetic interaction networks from quantitative phenotype data.
    Genome Biol. 2005;6(4):R38 PMID: 15833125
  26. DNA helicase gene interaction network defined using synthetic lethality analyzed by microarray.
    Nat Genet. 2003 Nov;35(3):277-86 PMID: 14566339
  27. Discovering functional relationships: biochemistry versus genetics.
    Trends Genet. 2005 Aug;21(8):424-7 PMID: 15982781
  28. Deletion of the SRS2 gene suppresses elevated recombination and DNA damage sensitivity in rad5 and rad18 mutants of Saccharomyces cerevisiae.
    Mutat Res. 2001 Jul 12;486(2):137-46 PMID: 11425518
  29. Functional profiling of the Saccharomyces cerevisiae genome.
    Nature. 2002 Jul 25;418(6896):387-91 PMID: 12140549
  30. Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease.
    Genes Dev. 2001 Oct 15;15(20):2730-40 PMID: 11641278
  31. Test of synergistic interactions among deleterious mutations in bacteria.
    Nature. 1997 Nov 27;390(6658):395-8 PMID: 9389477
  32. Genomic buffering mitigates the effects of deleterious mutations in bacteria.
    Nat Genet. 2005 Dec;37(12):1376-9 PMID: 16273106
  33. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis.
    Science. 1999 Aug 6;285(5429):901-6 PMID: 10436161
  34. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.
    Nat Genet. 2005 Sep;37(9):958-63 PMID: 16116422
  35. Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile.
    Cell. 2005 Nov 4;123(3):507-19 PMID: 16269340
  36. A genomewide screen in Saccharomyces cerevisiae for genes that suppress the accumulation of mutations.
    Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11529-34 PMID: 12972632
  37. Yeast MPH1 gene functions in an error-free DNA damage bypass pathway that requires genes from Homologous recombination, but not from postreplicative repair.
    Genetics. 2004 Apr;166(4):1673-86 PMID: 15126389
  38. Small fitness effects and weak genetic interactions between deleterious mutations in heterozygous loci of the yeast Saccharomyces cerevisiae.
    Genet Res. 2003 Aug;82(1):19-31 PMID: 14621268
  39. Recombination proteins in yeast.
    Annu Rev Genet. 2004;38:233-71 PMID: 15568977
  40. Mutations in recombinational repair and in checkpoint control genes suppress the lethal combination of srs2Delta with other DNA repair genes in Saccharomyces cerevisiae.
    Genetics. 2001 Feb;157(2):557-65 PMID: 11156978
  41. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  42. Genome-wide requirements for resistance to functionally distinct DNA-damaging agents.
    PLoS Genet. 2005 Aug;1(2):e24 PMID: 16121259
  43. Systematic interpretation of genetic interactions using protein networks.
    Nat Biotechnol. 2005 May;23(5):561-6 PMID: 15877074
  44. The synthetic genetic interaction spectrum of essential genes.
    Nat Genet. 2005 Oct;37(10):1147-52 PMID: 16155567
  45. Deleterious mutations and the evolution of sexual reproduction.
    Nature. 1988 Dec 1;336(6198):435-40 PMID: 3057385
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1061-4036
DOI
10.1038/ng1948
Published
2007-02-00
Epub
2007-00-07
Pages
199-206
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2716756
Subset
IM
Grants
NHGRI NIH HHS · R01 HG003224 · United States
NHGRI NIH HHS · R01 HG003224-01A2 · United States
NHGRI NIH HHS · R01 HG003224-02 · United States
NHGRI NIH HHS · R01 HG003224-03 · United States
Databases
SWISSPROT
P06778, P10862, P12954, P22134, P25301, P25454, P32849, P32863, P35187, P38257, P38326, P38751, P38850, P38953, P38957, P40465, P40562, P47050, P48562, Q04149, Q04659, Q06211, Q12098, Q12223, Q12318, Q99359
Corrections
CommentIn
PMID: 17392802
External Links
PubMed source DOI: 10.1038/ng1948 PMC Full Text View journal details
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