Unraveling DNA damage response-signaling networks through systems approaches

Genotoxic perturbation holds a central place in cancer formation and aging, but also is key to cancer therapy by irradiation or chemotherapeutic drugs. Sensing of DNA lesions initiates a highly complex DNA damage response (DDR). This response involves signaling cascades that activate appropriate damage repair pathways, arrest the cell cycle, and ultimately determine cell survival or death. The DDR must be integrated with ongoing signaling and housekeeping processes. With the emergence of high-throughput omics technologies, it has become clear that DNA damage-mediated responses penetrate far deeper than previously appreciated into virtually all cellular signaling pathways. Advances in the last decade have revealed a plethora of early DNA damage-induced changes in posttranslational modifications and subsequent alterations in gene expression profiles, and have provided a glimpse into the assorted rewiring of signal transduction cascades providing biomarkers for chemo- or radiosensitivity. At the same time, genome-wide RNAi screening has provided mechanistic insights into DDR signaling cascades and identified genes involved in mechanisms of cancer resistance to genotoxic therapies. Most recently, distinct omics datasets have been integrated, and sophisticated mathematical models have been applied to the DDR. Here, we review such recent advances that have widened and, in some cases, deepened our knowledge of DDR signaling.