Cited by 133Fungal and yeast genetics researchBioinformatics and Genomic NetworksGene Regulatory Network Analysis

Functional Overlap and Regulatory Links Shape Genetic Interactions between Signaling Pathways

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van Wageningen, Sake, Kemmeren, Patrick, Lijnzaad, Philip, Margaritis, Thanasis, Benschop, Joris J., de Castro, Inês J., van Leenen, Dik, Groot Koerkamp, Marian J.A. +17 more·2010·Cell

Abstract

To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.

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Crossref · 10.1016/j.cell.2010.11.021

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  • A common neomorphic behavior, similar to one observed in yeast, occurred when a perturbation with little transcriptional effect alone enhanced the effects of a second perturbation (e.g., FEV/CBFA2T3, d=0.74).

    “A common neomorphic behavior, similar to one observed in yeast (22), occurred when a perturbation that had little transcriptional effect on its own appeared to enhance the effects of a second perturbation (e.g. FEV/CBFA2T3, d = 0.74, fig. S11E).”

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Authors
van Wageningen, S., Kemmeren, P., Lijnzaad, P., Margaritis, T., Benschop, J. J., de Castro, I. J., van Leenen, D., Groot Koerkamp, M. J. A., Ko, C. W., Miles, A. J., Brabers, N., Brok, M. O., Lenstra, T. L., Fiedler, D., Fokkens, L., Aldecoa, R., Apweiler, E., Taliadouros, V., Sameith, K., van de Pasch, L. A. L., van Hooff, S. R., Bakker, L. V., Krogan, N. J., Snel, B., & Holstege, F. C. P.
Affiliations
  • University Medical Center Utrecht (NL)
  • Netherlands Bioinformatics Centre (NL)
  • University of California, San Francisco (US)
  • Utrecht University (NL)
Corresponding author
Holstege, Frank C.P.
Venue
Cell
Publisher
Elsevier BV
Published
2010-12
Volume
143
Issue
6
Pages
991-1004
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2112441403
Cited by
133
References
75
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 3 · 2019: 12 · 2018: 7 · 2017: 11 · 2016: 7 · 2015: 12 · 2014: 16 · 2013: 17 · 2012: 13
FWCI
5.73
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (05071057, 81702015, 91106009, 016.108.607)
  • National Institute of General Medical Sciences (R01GM084448)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
synthetic genetic interactions, functional overlap, regulatory modules, repression, paralogs, Saccharomyces cerevisiae, gene expression profiling
MeSH terms
Epistasis, Genetic, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphotransferases, Saccharomyces cerevisiae, Signal Transduction, Gene Expression Profiling

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