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  - 
TY  - JOUR
A1  - Schumann, Sarah
A1  - Eberlein, Uta
A1  - Muhtadi, Razan
A1  - Lassmann, Michael
A1  - Scherthan, Harry
T1  - DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223
JF  - Scientific Reports
N2  - Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.
KW  - alpha particles
KW  - blood
KW  - DNA Breaks
KW  - double-stranded
KW  - gamma rays
KW  - healthy volunteers
KW  - humans
KW  - leukocytes
KW  - radiation effects
KW  - radium
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175596
VL  - 8
IS  - 2286
ER  -