ATM acts downstream of ATR in the DNA damage response signaling of bystander cells

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 -