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Nucleic Acids Res. 2013 Dec;41(22):10334-44. doi: 10.1093/nar/gkt833. Epub 2013 Sep 14.

ATR kinase activation in G1 phase facilitates the repair of ionizing radiation-induced DNA damage.

Author information

1
Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Department of Cell Biology and Physiology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA and Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Abstract

The kinase ATR is activated by RPA-coated single-stranded DNA generated at aberrant replicative structures and resected double strand breaks. While many hundred candidate ATR substrates have been identified, the essential role of ATR in the replicative stress response has impeded the study of ATR kinase-dependent signalling. Using recently developed selective drugs, we show that ATR inhibition has a significantly more potent effect than ATM inhibition on ionizing radiation (IR)-mediated cell killing. Transient ATR inhibition for a short interval after IR has long-term consequences that include an accumulation of RPA foci and a total abrogation of Chk1 S345 phosphorylation. We show that ATR kinase activity in G1 phase cells is important for survival after IR and that ATR colocalizes with RPA in the absence of detectable RPA S4/8 phosphorylation. Our data reveal that, unexpectedly, ATR kinase inhibitors may be more potent cellular radiosensitizers than ATM kinase inhibitors, and that this is associated with a novel role for ATR in G1 phase cells.

PMID:
24038466
PMCID:
PMC3905881
DOI:
10.1093/nar/gkt833
[Indexed for MEDLINE]
Free PMC Article

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