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Elucidation of the Clustered Nano-Architecture of Radiation-Induced DNA Damage Sites and Surrounding Chromatin in Cancer Cells: A Single Molecule Localization Microscopy Approach
- 1.0542178 - BFÚ 2022 RIV CH eng J - Journal Article
Hausmann, M. - Falk, Martin - Neitzel, Ch. - Hofmann, A. - Biswas, A. - Gier, T. - Falková, Iva - Heermann, D.W. - Hildenbrand, G.
Elucidation of the Clustered Nano-Architecture of Radiation-Induced DNA Damage Sites and Surrounding Chromatin in Cancer Cells: A Single Molecule Localization Microscopy Approach.
International Journal of Molecular Sciences. Roč. 22, č. 7 (2021), č. článku 3636. E-ISSN 1422-0067
R&D Projects: GA ČR GC20-04109J
Institutional support: RVO:68081707
Keywords : topology of DNA double strand breaks * nano-architecture * ionizing radiation-induced foci (IRIF) * chromatin rearrangements after irradiation * single molecule localization microscopy (SMLM)
Subject RIV: CE - Biochemistry
OBOR OECD: Biochemistry and molecular biology
Impact factor: 4.556, year: 2019
In cancer therapy, the application of (fractionated) harsh radiation treatment is state of the art for many types of tumors. However, ionizing radiation is a double-edged sword-it can kill the tumor but can also promote the selection of radioresistant tumor cell clones or even initiate carcinogenesis in the normal irradiated tissue. Individualized radiotherapy would reduce these risks and boost the treatment, but its development requires a deep understanding of DNA damage and repair processes and the corresponding control mechanisms. DNA double strand breaks (DSBs) and their repair play a critical role in the cellular response to radiation. In previous years, it has become apparent that, beyond genetic and epigenetic determinants, the structural aspects of damaged chromatin (i.e., not only of DSBs themselves but also of the whole damage-surrounding chromatin domains) form another layer of complex DSB regulation. In the present article, we summarize the application of super-resolution single molecule localization microscopy (SMLM) for investigations of these structural aspects with emphasis on the relationship between the nano-architecture of radiation-induced repair foci (IRIFs), represented here by gamma H2AX foci, and their chromatin environment. Using irradiated HeLa cell cultures as an example, we show repair-dependent rearrangements of damaged chromatin and analyze the architecture of gamma H2AX repair clusters according to topological similarities. Although HeLa cells are known to have highly aberrant genomes, the topological similarity of gamma H2AX was high, indicating a functional, presumptively genome type-independent relevance of structural aspects in DSB repair. Remarkably, nano-scaled chromatin rearrangements during repair depended both on the chromatin domain type and the treatment. Based on these results, we demonstrate how the nano-architecture and topology of IRIFs and chromatin can be determined, point to the methodological relevance of SMLM, and discuss the consequences of the observed phenomena for the DSB repair network regulation or, for instance, radiation treatment outcomes.
Permanent Link: http://hdl.handle.net/11104/0319654
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