Nanostructure of clustered DNA damage in leukocytes after in-solution irradiation with the alpha emitter Ra-223
Please always quote using this URN: urn:nbn:de:bvb:20-opus-193038
- Background: Cancer patients are increasingly treated with alpha-particle-emitting radiopharmaceuticals. At the subcellular level, alpha particles induce densely spaced ionizations and molecular damage. Induction of DNA lesions, especially clustered DNA double-strand breaks (DSBs), threatens a cell's survival. Currently, it is under debate to what extent the spatial topology of the damaged chromatin regions and the repair protein arrangements are contributing. Methods: Super-resolution light microscopy (SMLM) in combination with cluster analysisBackground: Cancer patients are increasingly treated with alpha-particle-emitting radiopharmaceuticals. At the subcellular level, alpha particles induce densely spaced ionizations and molecular damage. Induction of DNA lesions, especially clustered DNA double-strand breaks (DSBs), threatens a cell's survival. Currently, it is under debate to what extent the spatial topology of the damaged chromatin regions and the repair protein arrangements are contributing. Methods: Super-resolution light microscopy (SMLM) in combination with cluster analysis of single molecule signal-point density regions of DSB repair markers was applied to investigate the nano-structure of DNA damage foci tracks of Ra-223 in-solution irradiated leukocytes. Results: Alpha-damaged chromatin tracks were efficiently outlined by γ-H2AX that formed large (super) foci composed of numerous 60–80 nm-sized nano-foci. Alpha damage tracks contained 60–70% of all γ-H2AX point signals in a nucleus, while less than 30% of 53BP1, MRE11 or p-ATM signals were located inside γ-H2AX damage tracks. MRE11 and p-ATM protein fluorescent tags formed focal nano-clusters of about 20 nm peak size. There were, on average, 12 (±9) MRE11 nanoclusters in a typical γ-H2AX-marked alpha track, suggesting a minimal number of MRE11-processed DSBs per track. Our SMLM data suggest regularly arranged nano-structures during DNA repair in the damaged chromatin domain.…
Author: | Harry Scherthan, Jin-Ho Lee, Emanuel Maus, Sarah Schumann, Razan Muhtadi, Robert Chojowski, Matthias Port, Michael Lassmann, Felix Bestvater, Michael Hausmann |
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URN: | urn:nbn:de:bvb:20-opus-193038 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Klinik und Poliklinik für Nuklearmedizin |
Language: | English |
Parent Title (English): | Cancers |
ISSN: | 2072-6694 |
Year of Completion: | 2019 |
Volume: | 11 |
Issue: | 12 |
Article Number: | 1877 |
Source: | Cancers (2019) 11:12, 1877. https://doi.org/10.3390/cancers11121877 |
DOI: | https://doi.org/10.3390/cancers11121877 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | DNA repair; DSB focus substructure; Single Molecule Localization Microscopy (SMLM); complex DNA damage; high LET irradiation |
Release Date: | 2022/04/28 |
Date of first Publication: | 2019/11/26 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |