Abstract
The ataxia telangiectasia mutated (ATM) protein plays a central role in early stages of DNA double strand break (DSB) detection and controls cellular responses to this damage. Although hypersensitive to ionizing radiation-induced clonogenic lethality, ataxia telangiectasia cells are paradoxically deficient in their ability to undergo ionizing radiation-induced apoptosis. This contradiction illustrates the complexity of the central role of ATM in DNA damage response and the need for further understanding. Certain hexavalent chromium (Cr(VI)) compounds are implicated as occupational respiratory carcinogens at doses that are both genotoxic and cytotoxic. Cr(VI) induces a broad spectrum of DNA damage, but Cr(VI)-induced DSBs have not been reported. Here, we examined the role of ATM in the cellular response to Cr(VI) and found that Cr(VI) activates ATM. We also show that physiological targets of ATM, p53 Ser-15 and Chk2 Thr-68, were phosphorylated by Cr(VI) exposure in an ATM-dependent fashion. We found that ATM-/- cells were markedly resistant to Cr(VI)-induced apoptosis but considerably more sensitive to Cr(VI)-induced clonogenic lethality than wild type cells, indicating that resistance to Cr(VI)-induced apoptosis did not confer a selective survival advantage. However, analysis of long term growth arrest revealed a striking difference: ATM-/- cells were markedly less able to recover from Cr(VI)-induced growth arrest. This indicates that terminal growth arrest is the fate of these apoptosis-resistant cells. In summary, ATM is involved in cellular response to a complex genotoxin that may not directly induce DSBs. Our data suggest that ATM is a major signal initiator for genotoxin-induced apoptosis but, paradoxically, also contributes to maintenance of cell survival by facilitating recovery/escape from terminal growth arrest. The results also strongly suggest that terminal growth arrest is not merely an extended or even irreversible form of checkpoint arrest, but instead an independent and unique cell fate pathway.
Highlights
The ataxia telangiectasia mutated (ATM) protein plays a central role in early stages of DNA double strand break (DSB) detection and controls cellular responses to this damage
Kinase Activity of ATM Was Enhanced after Cr(VI) Treatment—The lack of ATM protein in the ATMϪ/Ϫ and mutant cell lines was confirmed by immunoblotting analysis
ATM kinase has been shown to be activated in response to DNA DSBs, which can be induced by ionizing radiation (IR), radiomimetic agents, FIG. 8
Summary
The ataxia telangiectasia mutated (ATM) protein plays a central role in early stages of DNA double strand break (DSB) detection and controls cellular responses to this damage. Hypersensitive to ionizing radiation-induced clonogenic lethality, ataxia telangiectasia cells are paradoxically deficient in their ability to undergo ionizing radiation-induced apoptosis This contradiction illustrates the complexity of the central role of ATM in DNA damage response and the need for further understanding. The ATM protein has been shown to function in multiple biochemical pathways linking the recognition and repair of DNA double strand breaks (DSBs) to downstream cellular processes, such as activation of cell cycle checkpoints, DNA repair, and apoptosis [6] by phosphorylating numerous substrates including p53 [7], Brca1 [8], Chk2 [9], c-Abl [10], and replication protein A [11]. In a recent study, we showed that telomeraseimmortalized human cell populations exposed to Cr(VI) exhibit a different spectrum of responses, which include clonogenic survival, terminal growth arrest or apoptosis, depending on the extent of DNA damage. The regaining of replicative potential after genotoxic exposure was attributable to either escape from, or resistance to, terminal growth arrest or apoptosis [30]
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