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A Systems Approach to Mapping DNA Damage Response Pathways
Christopher T. Workman,1*H. Craig Mak,1*Scott McCuine,1Jean-Bosco Tagne,2Maya Agarwal,1Owen Ozier,2Thomas J. Begley,3Leona D. Samson,4Trey Ideker1
Failure of cells to respond to DNA damage is a primary eventassociated with mutagenesis and environmental toxicity. To mapthe transcriptional network controlling the damage response,we measured genomewide binding locations for 30 damage-relatedtranscription factors (TFs) after exposure of yeast to methyl-methanesulfonate(MMS). The resulting 5272 TF-target interactions revealed extensivechanges in the pattern of promoter binding and identified damage-specificbinding motifs. As systematic functional validation, we identifiedinteractions for which the target changed expression in wild-typecells in response to MMS but was nonresponsive in cells lackingthe TF. Validated interactions were assembled into causal pathwaymodels that provide global hypotheses of how signaling, transcription,and phenotype are integrated after damage.
1 University of California San Diego, La Jolla, CA 92093, USA. 2 Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA. 3 University of Albany–State University at New York, Rensselaer, NY 12144, USA. 4 Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: trey{at}bioeng.ucsd.edu
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