Functional Overlap and Regulatory Links Shape Genetic Interactions between Signaling Pathways

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.11.021 Byline: Sake van Wageningen (1), Patrick Kemmeren (1), Philip Lijnzaad (1)(4), Thanasis Margaritis (1), Joris J. Benschop (1), InA*s J. de Castro (1), Dik van Leenen (1), Marian J.A. Groot Koerkamp (1), Cheuk W. Ko (1), Antony J. Miles (1), Nathalie Brabers (1), Mariel O. Brok (1), Tineke L. Lenstra (1), Dorothea Fiedler (2), Like Fokkens (3), Rodrigo Aldecoa (1), Eva Apweiler (1), Virginia Taliadouros (1), Katrin Sameith (1), Loes A.L. van de Pasch (1), Sander R. van Hooff (1), Linda V. Bakker (1)(4), Nevan J. Krogan (2), Berend Snel (3), Frank C.P. Holstege (1) Keywords: CELLBIO; SIGNALING 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. Author Affiliation: (1) Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands (2) Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA (3) Theoretical Biology and Bioinformatics, Department of Biology, Science Faculty, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands (4) Netherlands Bioinformatics Centre, Geert Grooteplein 28, 6525 GA, Nijmegen, The Netherlands Article History: Received 29 January 2010; Revised 20 September 2010; Accepted 9 November 2010 Article Note: (miscellaneous) Published: December 9, 2010