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Science 330 (6009): 1385-1389

Copyright © 2010 by the American Association for the Advancement of Science

Rewiring of Genetic Networks in Response to DNA Damage

Sourav Bandyopadhyay,1 Monika Mehta,2 Dwight Kuo,3 Min-Kyung Sung,4 Ryan Chuang,3 Eric J. Jaehnig,5 Bernd Bodenmiller,6 Katherine Licon,1 Wilbert Copeland,3 Michael Shales,7 Dorothea Fiedler,7,8 Janusz Dutkowski,1 Aude Guénolé,9 Haico van Attikum,9 Kevan M. Shokat,7,8 Richard D. Kolodner,5,1,10 Won-Ki Huh,4 Ruedi Aebersold,6 Michael-Christopher Keogh,2,* Nevan J. Krogan,7,* Trey Ideker1,3,10,*

Abstract: Although cellular behaviors are dynamic, the networks that govern these behaviors have been mapped primarily as static snapshots. Using an approach called differential epistasis mapping, we have discovered widespread changes in genetic interaction among yeast kinases, phosphatases, and transcription factors as the cell responds to DNA damage. Differential interactions uncover many gene functions that go undetected in static conditions. They are very effective at identifying DNA repair pathways, highlighting new damage-dependent roles for the Slt2 kinase, Pph3 phosphatase, and histone variant Htz1. The data also reveal that protein complexes are generally stable in response to perturbation, but the functional relations between these complexes are substantially reorganized. Differential networks chart a new type of genetic landscape that is invaluable for mapping cellular responses to stimuli.

1 Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3 Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
4 School of Biological Sciences and Research Center for Functional Cellulomics, Institute of Microbiology, Seoul National University, 151-742 Seoul, Republic of Korea.
5 Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6 Institute of Molecular Systems Biology, ETH Zürich, Zürich CH 8093, Switzerland, and Faculty of Science, University of Zürich, Zürich CH 8057, Switzerland.
7 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
8 Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
9 Department of Toxicogenetics, Leiden University Medical Center, Leiden, Netherlands.
10 The Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

* To whom correspondence should be addressed. E-mail: tideker{at}ucsd.edu (T.I.); krogan{at}cmp.ucsf.edu (N.J.K.); michael.keogh{at}einstein.yu.edu (M.-C.K.)


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