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New insights into cooperation of micro- and nano-scale elementary structural chromatin units in decision-making on DNA damage repair pathway (NANOREP)

Subject Area Nuclear Medicine, Radiotherapy, Radiobiology
Biophysics
Term from 2019 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 432117611
 
Final Report Year 2024

Final Report Abstract

The project investigated the extent to which the spatial organisation of chromatin, i.e. the genome architecture and its dynamics, are subject to regulatory criteria and thus intervene in the regulation of repair processes alongside epigenetics. This would mean that the chromatin organisation would have an influence on radiation sensitivity as well as on the accessibility of repair proteins and thus also determine the repair pathway at a particular site of damage. Using Single Molecule Localisation Microscopy (SMLM) and mathematical evaluation methods, such as Ripley statistics of pairwise point distances, persistent homology, persistent imaging and principal component analysis, the chromatin organisation as a whole (heterochromatin, ALU regions) and the spatial organisation of double-strand break damage markers (γH2AX, MRE11, 53BP1, Rad51) were investigated. Appropriate software tools were established and applied to selected examples. Using cell lines as model systems, it was shown that in the topological network the mesh structure of ALU regions or heterochromatin differs significantly by cell type in the latent space of the first two principal components. After damage induction by low-LET or high-LET radiation, it was found in fibroblasts that the chromatin organisation changes during the repair of DNA damage in such a way that it undergoes a cycle in the latent space of the first two main components and returns to the initial organisation after successful repair. This has not always been observed in tumour cells. In fact, it has been shown that they can exhibit a completely altered chromatin organisation after 24 hours. After the induction of double-strand breaks, it was shown that γH2AX or 53BP1 clusters exhibited a change in topology with an almost constant diameter. This change could also be described by a cycle in the latent space of the first two main components. The final configuration after successful repair corresponded to typical topologies of the γH2AX/53BP1 cluster background of non-irradiated cells. Fibroblasts and selected tumour cell systems did not differ. In contrast, the type of radiation made the difference. While a large change in the latent space was observed after low-LET irradiation, the changes were relatively small with high-LET irradiation. In addition to the experimental microscopic data, computer analysis of databases showed that there are short sequence motifs that favour certain folding and packaging properties of the chromatin organisation. The presence of LINEs (L1) and SINEs (ALU) in the context of chromatin organisation and DNA repair was also investigated.

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