Workman Christopher T, Mak H Craig, McCuine Scott, Tagne Jean-Bosco, Agarwal Maya, Ozier Owen, Begley Thomas J, Samson Leona D, Ideker Trey
University of California San Diego, La Jolla, CA 92093, USA.
Science. 2006 May 19;312(5776):1054-9. doi: 10.1126/science.1122088.
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.
细胞对DNA损伤无反应是与诱变和环境毒性相关的主要事件。为了绘制控制损伤反应的转录网络，我们在酵母暴露于甲基磺酸甲酯（MMS）后测量了30种损伤相关转录因子（TF）的全基因组结合位点。由此产生的5272个TF-靶标相互作用揭示了启动子结合模式的广泛变化，并确定了损伤特异性结合基序。作为系统的功能验证，我们确定了这样的相互作用：其靶标在野生型细胞中响应MMS而改变表达，但在缺乏该TF的细胞中无反应。经过验证的相互作用被组装成因果通路模型，这些模型提供了损伤后信号传导、转录和表型如何整合的全局假设。
