title: Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein. Requirement of ATM for both apoptosis and recovery from terminal growth arrest.
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.
authors.affiliation: Department of Pharmacology, Program in Molecular and Cellular Oncology, The George Washington University Medical Center, Washington, D. C. 20037, USA.
authors.forename: Linan
authors.initials: L
authors.lastname: Ha
authors.forename: Susan
authors.initials: S
authors.lastname: Ceryak
authors.forename: Steven R
authors.initials: SR
authors.lastname: Patierno
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002455:Cell Division; D019070:Cell Lineage; D064447:Checkpoint Kinase 2; D002840:Chromates / Q000494:pharmacology; D002857:Chromium / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010718:Phosphatidylserines / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012694:Serine / Q000737:chemistry; D017670:Sodium Compounds / Q000494:pharmacology; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D002840:Chromates; D004268:DNA-Binding Proteins; D006657:Histones; D010718:Phosphatidylserines; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002857:Chromium; D013912:Threonine; D012694:Serine; C028982:sodium chromate(VI); D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D001973:Bromodeoxyuridine