| DNA damage responses play a significant role in maintaining the general genome stability and preventing the development of cancer in cells. The realization that DNA damage triggers responses from a network of interacting pathways in the cell marks a milestone in the study of the DNA repair systems. The main goal of my research work is to develop computational approach to explore the activated signaling pathways associated with DNA damage response in cancer. We established the RepairPLAT, an integrative experimental platform for comprehensive studies of the regulatory control mechanisms of DNA damage response in cancer.; RepairPLAT platform has three components: (1) RepairNET, a protein-protein interaction network associated with the DNA damage response. RepairNET currently contains more than 1,200 proteins with over 2,300 functional interactions. It was assembled by using a protocol that involved computational data mining of MEDLINE as well as extracting data from various databases like SwissProt, DIP, and Pfam. (2) RepairCHIP, a 60-mer oligonucleotide microarray chip contains genes corresponding to the proteins in RepairNET. In contrast to generic arrays, RepairCHIP contains genes of known functional relationship, which significantly reduces the complications for microarray data interpretation. (3) RepairPATH, a pathway-exploration algorithm that integrates RepairNET with the gene expression profiles derived from microarray data. Based on the observation that co-functional proteins often exhibit correlated gene expression profiles, RepairPATH identifies the activated signaling pathways in cancer by systematically searching the RepairNET for proteins with significantly correlated gene expression profiles. Analyzing the gene expression profiles of breast cancer by using RepairPATH, we found distinct similarities and differences in the activated signaling pathways between the samples from the patients who developed metastases and the samples from the patients who were disease free within 5 years.; With the RepairPLAT platform, we first explored the activated DNA damage response pathways in cancer on a global scale, and then biological function of these potentially activated pathways were verified at molecular level by using biochemical assays. |
