The ATM-SMC1 pathway is essential for activation of the chromium[VI]-induced S-phase checkpoint |
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Authors: | Wakeman Timothy P Kim Wan-Ju Callens Shannon Chiu Arthur Brown Kevin D Xu Bo |
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Institution: | Department of Biochemistry and Molecular Biology, Stanley S. Scott Cancer Center, LSU Health Sciences Center, 533 Bolivar Street, Room 406 CSRB, New Orleans, LA 70112, USA. |
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Abstract: | Hexavalent chromium (CrVI]) is a common industrial waste product, an environmental pollutant, and a recognized human carcinogen. Following cellular uptake, CrVI] can cause DNA damage, however, the mechanisms by which mammalian cells respond to Cr-induced DNA damage remain to be elucidated. Using single cell gel electrophoresis (e.g., Comet Assay) and immunofluoresence microscopy to detect the presence of gamma-H2AX foci, we find that CrVI] induces DNA double-strand breaks similar to ionizing radiation (IR). We also demonstrated that ataxia telangiectasia mutated (ATM) is activated in response to CrVI] and exposure to CrVI] triggers a dose and ATM-dependent S-phase arrest. Further, we document that ATM is required for phosphorylation of the structural maintenance of chromosome protein 1 (SMC1). Finally, we find that ATM-dependent phosphorylation of SMC1 is required to facilitate S-phase cell-cycle arrest in response to CrVI] exposure. Collectively, these results indicate that the ATM-SMC1 pathway plays a critical role in cellular response to CrVI]. |
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