A systems approach to mapping DNA damage response pathways.
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.
Workman
Christopher T
CT
University of California San Diego, La Jolla, CA 92093, USA.
Mak
H Craig
HC
McCuine
Scott
S
Tagne
Jean-Bosco
JB
Agarwal
Maya
M
Ozier
Owen
O
Begley
Thomas J
TJ
Samson
Leona D
LD
Ideker
Trey
T
D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004271:DNA, Fungal; D005656:Fungal Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D008741:Methyl Methanesulfonate; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012440:Saccharomyces; D015398:Signal Transduction; D013598:Systems Theory; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D004271:DNA, Fungal; D005656:Fungal Proteins; D014157:Transcription Factors; D008741:Methyl Methanesulfonate