Nanostructure of clustered DNA damage in leukocytes after in-solution irradiation with the alpha emitter Ra-223
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&a...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
26 November 2019
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| In: |
Cancers
Year: 2019, Volume: 11, Issue: 12 |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers11121877 |
| Online Access: | Verlag, Volltext: https://doi.org/10.3390/cancers11121877 Verlag: https://www.mdpi.com/2072-6694/11/12/1877 
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| Author Notes: | Harry Scherthan, Jin-Ho Lee, Emanuel Maus, Sarah Schumann, Razan Muhtadi, Robert Chojowski, Matthias Port, Michael Lassmann, Felix Bestvater and Michael Hausmann |
| Summary: | 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 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. |
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| Item Description: | Gesehen am 18.02.2020 |
| Physical Description: | Online Resource |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers11121877 |