ATM acts downstream of ATR in the DNA damage response signaling of bystander cells
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ATM acts downstream of ATR in the DNA damage response signaling of bystander cells. / Burdak-Rothkamm, Susanne; Rothkamm, Kai; Prise, Kevin M.
In: CANCER RES, Vol. 68, No. 17, 01.09.2008, p. 7059-65.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - ATM acts downstream of ATR in the DNA damage response signaling of bystander cells
AU - Burdak-Rothkamm, Susanne
AU - Rothkamm, Kai
AU - Prise, Kevin M
PY - 2008/9/1
Y1 - 2008/9/1
N2 - This study identifies ataxia-telangiectasia mutated (ATM) as a further component of the complex signaling network of radiation-induced DNA damage in nontargeted bystander cells downstream of ataxia-telangiectasia and Rad3-related (ATR) and provides a rationale for molecular targeted modulation of these effects. In directly irradiated cells, ATR, ATM, and DNA-dependent protein kinase (DNA-PK) deficiency resulted in reduced cell survival as predicted by the known important role of these proteins in sensing DNA damage. A decrease in clonogenic survival was also observed in ATR/ATM/DNA-PK-proficient, nonirradiated bystander cells, but this effect was completely abrogated in ATR and ATM but not DNA-PK-deficient bystander cells. ATM activation in bystander cells was found to be dependent on ATR function. Furthermore, the induction and colocalization of ATR, 53BP1, ATM-S1981P, p21, and BRCA1 foci in nontargeted cells was shown, suggesting their involvement in bystander DNA damage signaling and providing additional potential targets for its modulation. 53BP1 bystander foci were induced in an ATR-dependent manner predominantly in S-phase cells, similar to gammaH2AX foci induction. In conclusion, these results provide a rationale for the differential modulation of targeted and nontargeted effects of radiation.
AB - This study identifies ataxia-telangiectasia mutated (ATM) as a further component of the complex signaling network of radiation-induced DNA damage in nontargeted bystander cells downstream of ataxia-telangiectasia and Rad3-related (ATR) and provides a rationale for molecular targeted modulation of these effects. In directly irradiated cells, ATR, ATM, and DNA-dependent protein kinase (DNA-PK) deficiency resulted in reduced cell survival as predicted by the known important role of these proteins in sensing DNA damage. A decrease in clonogenic survival was also observed in ATR/ATM/DNA-PK-proficient, nonirradiated bystander cells, but this effect was completely abrogated in ATR and ATM but not DNA-PK-deficient bystander cells. ATM activation in bystander cells was found to be dependent on ATR function. Furthermore, the induction and colocalization of ATR, 53BP1, ATM-S1981P, p21, and BRCA1 foci in nontargeted cells was shown, suggesting their involvement in bystander DNA damage signaling and providing additional potential targets for its modulation. 53BP1 bystander foci were induced in an ATR-dependent manner predominantly in S-phase cells, similar to gammaH2AX foci induction. In conclusion, these results provide a rationale for the differential modulation of targeted and nontargeted effects of radiation.
KW - Ataxia Telangiectasia Mutated Proteins
KW - Bystander Effect
KW - Cell Cycle Proteins/physiology
KW - Cell Line, Tumor
KW - DNA Damage
KW - DNA-Activated Protein Kinase/metabolism
KW - DNA-Binding Proteins/physiology
KW - Humans
KW - Immunohistochemistry
KW - Intracellular Signaling Peptides and Proteins/physiology
KW - Protein-Serine-Threonine Kinases/physiology
KW - Tumor Suppressor Proteins/physiology
KW - Tumor Suppressor p53-Binding Protein 1
U2 - 10.1158/0008-5472.CAN-08-0545
DO - 10.1158/0008-5472.CAN-08-0545
M3 - SCORING: Journal article
C2 - 18757420
VL - 68
SP - 7059
EP - 7065
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 17
ER -