TRIREME · Systems-Level, Multi-layer Understanding of Cellular Responses to Ionizing Radiation

The TRIREME project aims at developing and implementing a multidisciplinary strategy for a systems-level analysis of a cornerstone of cellular homeostasis – the DNA damage response (DDR). The DDR is a complex signaling network that is responsible for maintaining the stability and integrity of the cellular genome in the face of DNA damage. DDR defects underlie acute and chronic forms of human ailments that involve tissue degeneration, premature ageing, sensitivity to environmental agents and cancer predisposition. Importantly, many cancer treatment regimens are based on DNA damaging agents. Therefore, gaining systems-level understanding of the DDR is of paramount importance for human health. TRIREME brings together a multidisciplinary consortium of six world-leading researchers with long-standing expertise in the DDR, cell cycle control, functional genomics, proteomics and computational biology. It will focus on a prototypic DNA damage inducer – ionizing radiation (IR), used extensively in cancer radiotherapy. The critical IR-induced DNA lesion is the double strand break, which vigorously activates the DDR. We will systematically analyze the IR-induced network in all its major layers: gene expression, microRNA expression, the proteome, and key protein post-translational modifications. The analysis is aimed at obtaining a global view of the DDR, and identifying new players in the network. The data obtained by these different approaches will be integrated into coherent models using novel computational algorithms developed for TRIREME. To the best of our knowledge, such an analysis has not been applied before to mammalian systems. The results are expected to have far-reaching ramifications in various biomedical fields, with special importance for clinical oncology.