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Science 312 (5776): 1054-1059

Copyright © 2006 by the American Association for the Advancement of Science

A Systems Approach to Mapping DNA Damage Response Pathways

Christopher T. Workman,1* H. Craig Mak,1* Scott McCuine,1 Jean-Bosco Tagne,2 Maya Agarwal,1 Owen Ozier,2 Thomas J. Begley,3 Leona D. Samson,4 Trey Ideker1{dagger}

Abstract: Failure of cells to respond to DNA damage is a primary event associated with mutagenesis and environmental toxicity. To map the transcriptional network controlling the damage response, we measured genomewide binding locations for 30 damage-related transcription factors (TFs) after exposure of yeast to methyl-methanesulfonate (MMS). The resulting 5272 TF-target interactions revealed extensive changes in the pattern of promoter binding and identified damage-specific binding motifs. As systematic functional validation, we identified interactions for which the target changed expression in wild-type cells in response to MMS but was nonresponsive in cells lacking the TF. Validated interactions were assembled into causal pathway models 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.

{dagger} To whom correspondence should be addressed. E-mail: trey{at}bioeng.ucsd.edu


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