TY  - JOUR
A1  - Scherthan, Harry
A1  - Lee, Jin-Ho
A1  - Maus, Emanuel
A1  - Schumann, Sarah
A1  - Muhtadi, Razan
A1  - Chojowski, Robert
A1  - Port, Matthias
A1  - Lassmann, Michael
A1  - Bestvater, Felix
A1  - Hausmann, Michael
T1  - Nanostructure of clustered DNA damage in leukocytes after in-solution irradiation with the alpha emitter Ra-223
JF  - Cancers
N2  - 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.
KW  - complex DNA damage
KW  - DNA repair
KW  - high LET irradiation
KW  - Single Molecule Localization Microscopy (SMLM)
KW  - DSB focus substructure
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193038
SN  - 2072-6694
VL  - 11
IS  - 12
ER  -