The role of the DNA damage response protein kinase ataxia telangiectasia and Rad-3-related (ATR) in the cellular response to DNA damage during the replicative phase of the cell cycle has been extensively studied. However, little is known about ATR kinase function in cells that are not actively replicating DNA and which constitute most cells in the human body. Using small-molecule inhibitors of ATR kinase and overexpression of a kinase-inactive form of the enzyme, I show here that ATR promotes cell death in non-replicating/non-cycling cultured human cells exposed to N-acetoxy-2-acetylaminofluorene (NA-AAF), which generates bulky DNA adducts that block RNA polymerase movement. Immunoblot analyses of soluble protein extracts revealed that ATR and other cellular proteins containing SQ motifs become rapidly and robustly phosphorylated in non-cycling cells exposed to NA-AAF in a manner largely dependent on ATR kinase activity but independent of the essential nucleotide excision repair factor XPA. Although the topoisomerase I inhibitor camptothecin also activated ATR in non-cycling cells, other transcription inhibitors that do not directly damage DNA failed to do so. Interestingly, genetic and pharmacological inhibition of the XPB subunit of transcription factor IIH (TFIIH) prevented the accumulation of the single-stranded DNA binding protein RPA on damaged chromatin and severely abrogated ATR signaling in response to NA-AAF and camptothecin. Together, these results reveal a previously unknown role for TFIIH in ATR kinase activation in non-replicating, non-cycling cells.
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