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ATM Acts Downstream of ATR in the DNA Damage Response Signaling of Bystander Cells

¹ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom and ² Gray Cancer Institute, University of Oxford, Northwood, United Kingdom

Requests for reprints: Susanne Burdak-Rothkamm, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom. Phone: 44-28-9097-2943; Fax: 44-28-9097-2776; E-mail: s.burdakrothkamm{at}yahoo.co.uk.

Key Words: ataxia-telangiectasia and Rad3-related (ATR) • ataxia-telangiectasia mutated (ATM) • 53BP1 • DNA damage response • radiation-induced bystander signaling

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 H2AX foci induction. In conclusion, these results provide a rationale for the differential modulation of targeted and nontargeted effects of radiation. [Cancer Res 2008;68(17):7059–65]