Complex DNA lesions and their impact on cellular radiation response - Collar

Complex DNA lesions and their impact on cellular radiation response - Collar

The investigations will deepen our knowledge on the impact of radiation-induced complex DNA lesions with spinoffs for radiation protection and the development of new, advanced tumor therapy strategies.

The DNA double-strand-break (DSB), which is defined as a rupture in the double-stranded DNA molecule, is the most critical DNA lesion and when un- or misrepaired may lead to transformation or cell killing. For a DSB the chance to be accurately repaired strongly depends on its complexity. This complexity is defined by the nature and number of chemical alterations involved, its clustering or location in chromatin regions of different accessibility, as well as its association with DNA replication.

It is widely recognized that lesion complexity is a major determinant of many of the adverse effects of IR, but the risks associated with different levels of complexity and the role of complexity in the choice of DSB repair pathway remain conjectural. The latter is particularly relevant, as it is well-known that the pathways engaged in DSB processing show distinct and frequently inherent propensities for errors. Therefore, pathway-choice will define the types and levels of possible errors and thus also the associated risk for genomic alterations.

Here, we present a project designed to address the biological consequences of DSBs of different levels of complexity focusing on how complexity affects processing and the generation of processing-errors. In a highly coordinated effort, five expert Institutes and Clinics address specific facets of DSB complexity and cover in this way a spectrum of lesions encompassing all major candidates for adverse radiation effects. Importantly, the experimental design integrates a bioinformatics component analyzing the effect of DSB complexity on gene expression, as well as DNA sequence alterations from erroneous processing. The knowledge generated by the proposal will be important for our understanding of the mechanisms underpinning individual radiosensitivity differences, and relevant to radiation protection and individualized radiotherapy.

The proposed research will generate an environment that will strengthen the participating groups and as a result the field of Radiation Biology in Germany. Most notably though, it will generate a unique environment for recruiting and training young investigators, as well for retaining in the field excellent graduate students as postdoctoral fellows.