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A Systems Approach to Mapping DNA Damage Response Pathways

Science (2006) Vol. 312. no. 5776, pp. 1054 - 1059 [PubMed] [Science online] [PDF]

Christopher T. Workman1#*, H. Craig Mak1*, Scott McCuine1, Jean-Bosco Tagne2,
Maya Agarwal1, Owen Ozier2, Thomas J. Begley3, Leona D. Samson4, Trey Ideker1†

Download: Supporting Online Material (PDF document with Methods and Figures)


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 genome-wide binding locations for 30 damage-related transcription factors (TFs) after exposure of yeast to methyl-methanesulfonate. The resulting 5,272 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 non-responsive 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
2 Whitehead Institute for Biomedical Research, Cambridge, MA 02139
3 University of Albany-State University of New York, Rensselaer, NY 12144
4 Massachusetts Institute of Technology, Cambridge, MA 02139
* These authors contributed equally to the manuscript.
# Present address: Center for Biological Sequence Analysis, The Technical University of Denmark, Lyngby, Denmark
To whom correspondence should be addressed. E-mail: trey@bioeng.ucsd.edu