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Nanostructure of clustered DNA damage in leukocytes after in-solution irradiation with the alpha emitter Ra-223
Zitieren Sie bitte immer diese 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.…
Autor(en): | 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 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Klinik und Poliklinik für Nuklearmedizin |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Cancers |
ISSN: | 2072-6694 |
Erscheinungsjahr: | 2019 |
Band / Jahrgang: | 11 |
Heft / Ausgabe: | 12 |
Aufsatznummer: | 1877 |
Originalveröffentlichung / Quelle: | Cancers (2019) 11:12, 1877. https://doi.org/10.3390/cancers11121877 |
DOI: | https://doi.org/10.3390/cancers11121877 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | DNA repair; DSB focus substructure; Single Molecule Localization Microscopy (SMLM); complex DNA damage; high LET irradiation |
Datum der Freischaltung: | 28.04.2022 |
Datum der Erstveröffentlichung: | 26.11.2019 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |