BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells
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BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells. / Burdak-Rothkamm, Susanne; Rothkamm, Kai; McClelland, Keeva; Al Rashid, Shahnaz T; Prise, Kevin M.
In: CANCER LETT, Vol. 356, No. 2 Pt B, 28.01.2015, p. 454-61.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells
AU - Burdak-Rothkamm, Susanne
AU - Rothkamm, Kai
AU - McClelland, Keeva
AU - Al Rashid, Shahnaz T
AU - Prise, Kevin M
N1 - Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
PY - 2015/1/28
Y1 - 2015/1/28
N2 - Radiotherapy is an important treatment option for many human cancers. Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers. The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects. This study aims to elucidate radiation-induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting. Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine (BrdU) nuclear foci detection at sites of single stranded DNA. γH2AX co-localised with these BrdU foci. BRCA1 and FANCD2 foci formed in T98G bystander cells. Using ATR mutant F02-98 hTERT and ATM deficient GM05849 fibroblasts it could be shown that ATR but not ATM was required for the recruitment of FANCD2 to sites of replication associated DNA damage in bystander cells whereas BRCA1 bystander foci were ATM-dependent. Phospho-Chk1 foci formation was observed in T98G bystander cells. Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor UCN-01 but increased radioresistance of bystander cells. This study identifies BRCA1, FANCD2 and Chk1 as potential targets for the modulation of radiation response in bystander cells. It adds to our understanding of the key molecular events propagating out-of-field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation.
AB - Radiotherapy is an important treatment option for many human cancers. Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers. The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects. This study aims to elucidate radiation-induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting. Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine (BrdU) nuclear foci detection at sites of single stranded DNA. γH2AX co-localised with these BrdU foci. BRCA1 and FANCD2 foci formed in T98G bystander cells. Using ATR mutant F02-98 hTERT and ATM deficient GM05849 fibroblasts it could be shown that ATR but not ATM was required for the recruitment of FANCD2 to sites of replication associated DNA damage in bystander cells whereas BRCA1 bystander foci were ATM-dependent. Phospho-Chk1 foci formation was observed in T98G bystander cells. Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor UCN-01 but increased radioresistance of bystander cells. This study identifies BRCA1, FANCD2 and Chk1 as potential targets for the modulation of radiation response in bystander cells. It adds to our understanding of the key molecular events propagating out-of-field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation.
KW - Ataxia Telangiectasia Mutated Proteins/genetics
KW - BRCA1 Protein/metabolism
KW - Blotting, Western
KW - Brain Neoplasms/genetics
KW - Bystander Effect/genetics
KW - Cell Proliferation/radiation effects
KW - Checkpoint Kinase 1
KW - DNA Damage/genetics
KW - DNA Repair/genetics
KW - DNA Replication/genetics
KW - Fanconi Anemia Complementation Group D2 Protein/metabolism
KW - Flow Cytometry
KW - Glioma/genetics
KW - Humans
KW - Immunoenzyme Techniques
KW - Mutation/genetics
KW - Phosphorylation/radiation effects
KW - Protein Kinases/metabolism
KW - Signal Transduction/radiation effects
KW - Tumor Cells, Cultured
KW - X-Rays
U2 - 10.1016/j.canlet.2014.09.043
DO - 10.1016/j.canlet.2014.09.043
M3 - SCORING: Journal article
C2 - 25304378
VL - 356
SP - 454
EP - 461
JO - CANCER LETT
JF - CANCER LETT
SN - 0304-3835
IS - 2 Pt B
ER -