Gefördert durch: BMBF / 02NUK043 – 2,7 Mio. €

Laufzeit: 2015 bis 2020

Verantwortlicher Projektleiter: Dr. R. Kriehuber

Ziele

Zentrales Ziel des Vorhabens ist die Charakterisierung der zellzyklusabhängigen zellulären DNA-Schadensantwort nach Induktion von DNA-Doppelstrangbrüchen unterschiedlicher Komplexität in Abhängigkeit der Lokalisation des Schadens im Chromatin. Hierbei soll im Besonderen aufgeklärt werden, welche Faktoren die Auswahl der involvierten Reparaturprozesse bestimmen und inwieweit die unterschiedliche Komplexität der DNA-Läsionen die Güte (Fehlerhaftigkeit) der Reparatur beeinflussen und wie dies sich in der zyto- und gentoxischen Schädigung der Zellen widerspiegelt.

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, their clustering and the location in chromatin regions of different accessibility.

It is widely recognized that lesion complexity is a major determinant of many of the adverse effects of IR, but the risks for the cell 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, the choice of a repair pathway for the processing of any given DSB 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, four expert Institutes and Clinics address specific facets of DSB complexity and cover in this way a spectrum of lesions encompassing most 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.

• Forschungszentrum Jülich GmbH
- Department of Safety and Radiation Protection (Dr. R. Kriehuber)
• University Duisburg-Essen
- Department of Radiation Therapy (Prof. M. Stuschke)
- Institute of Medical Radiation Biology (Prof. G. Iliakis)
• University of Rostock
- Systems Biology and Bioinformatics (Prof. O. Wolkenhauer)