TY  - JOUR
A1  - Rall, Melanie
A1  - Kraft, Daniela
A1  - Volcic, Meta
A1  - Cucu, Aljona
A1  - Nasonova, Elena
A1  - Taucher-Scholz, Gisela
A1  - Bönig, Halvard-Björn
A1  - Wiesmüller, Lisa
A1  - Fournier, Claudia
T1  - Impact of charged particle exposure on homologous dna double-strand break repair in human blood-derived cells
T2  - Frontiers in oncology
N2  - Ionizing radiation generates DNA double-strand breaks (DSB) which, unless faithfully repaired, can generate chromosomal rearrangements in hematopoietic stem and/or progenitor cells (HSPC), potentially priming the cells towards a leukemic phenotype. Using an enhanced green fluorescent protein (EGFP)-based reporter system, we recently identified differences in the removal of enzyme-mediated DSB in human HSPC versus mature peripheral blood lymphocytes (PBL), particularly regarding homologous DSB repair (HR). Assessment of chromosomal breaks via premature chromosome condensation or γH2AX foci indicated similar efficiency and kinetics of radiation-induced DSB formation and rejoining in PBL and HSPC. Prolonged persistence of chromosomal breaks was observed for higher LET charged particles which are known to induce more complex DNA damage compared to X-rays. Consistent with HR deficiency in HSPC observed in our previous study, we noticed here pronounced focal accumulation of 53BP1 after X-ray and carbon ion exposure (intermediate LET) in HSPC versus PBL. For higher LET, 53BP1 foci kinetics was similarly delayed in PBL and HSPC suggesting similar failure to repair complex DNA damage. Data obtained with plasmid reporter systems revealed a dose- and LET-dependent HR increase after X-ray, carbon ion and higher LET exposure, particularly in HR-proficient immortalized and primary lymphocytes, confirming preferential use of conservative HR in PBL for intermediate LET damage repair. HR measured adjacent to the leukemia-associated MLL breakpoint cluster sequence in reporter lines revealed dose dependency of potentially leukemogenic rearrangements underscoring the risk of leukemia-induction by radiation treatment.
KW  - breakpoint cluster region
KW  - charged particles
KW  - chromosomal breaks
KW  - radiation damage response
KW  - DNA double-strand break repair
KW  - hematopoietic stem and progenitor cells
KW  - radiation-induced leukemia
Y1  - 2015
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/32678
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-326783
SN  - 2234-943X
N1  - Copyright: © 2015 Rall, Kraft, Volcic, Cucu, Nasonova, Taucher-Scholz, Bönig, Wiesmüller and Fournier. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)http://creativecommons.org/licenses/by/4.0/ . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
VL  - 5
PB  - Frontiers Media
CY  - Lausanne
ER  -