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A systems approach to mapping DNA damage response pathways.

Authors
  • Ct, Workman
  • Hc, Mak
  • S, Mccuine
  • Jb, Tagne
  • M, Agarwal
  • O, Ozier
  • Tj, Begley
  • Ld, Samson
  • Trey Ideker
Type
Published Article
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Volume
312
Issue
5776
Pages
1054–1059
Source
Ideker Lab
License
Unknown

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.

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