We are currently applying genome-scale approaches to derive and test a network model of the eukaryotic DNA damage response. Failure of cells to respond to DNA damage is a primary step in the onset of cancer and is a key mechanism of toxicity by pharmacologic agents. Consequently, cells have evolved complex repair and stress responses that are highly conserved across the eukaryotic kingdom, from yeast to humans. This feature of DNA damage response permits us to focus initial studies on the yeast Saccharomyces cerevisiae - impacting our basic understanding of cancer progression while keeping within an organism for which systems-level data are easily obtained. Our analysis involves: Exploring how the cell's transcriptional network undergoes remodeling between DNA-damaging and non-damaging conditions (ChIP-seq), and Collecting expression profiles in response to deleting each of a set of transcription factors (TFs) associated with DNA damage repair. This project is providing unique opportunities for validating and extending our modeling approaches and, if successful, will pave the way for systems modeling of a wide variety of diseases and cellular processes. A model resulting from our investigations is shown in Figure 1 [Workman et al. Science 2006].

We are also collaborating with a number of groups to study networks underlying viral infection [Konig et al. Cell 2008 and Bandyopadhyay et al. 2006].

This project is funded by grant ES014811.