The Atm-Smc1 Pathway Is Essential for Activation of the Chromium[vi]-Induced S-Phase Checkpoint
Hexavalent chromium (Cr[VI] is a common industrial waste product, an environmental pollutant, and a recognized human carcinogen. Following cellular uptake, Cr[VI] can cause DNA damage, however, the mechanisims 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 y-H2AX foci, we find that Cr[VI] induces DNA double-strand breaks similar to ionizing radiation (IR). We also demonstrated that ataxia telangiectasia mutated (ATM) is activated in response to Cr[VI] and exposure to Cr[VI] triggers a dose and ATM-dependent S-phase arrest. Further, we document that ATM is required for phosphorylation of the structural maintenance of chromosomal protein 1 (SMC1). Finally, we found that ATM-dependent phosphorylation of SMC1 is required S-phase cell-cycle arrest in response to Cr[VI] exposure. Collectively, these results indicated that the ATM-SMC1 pathway plays a critical role in cellular response to Cr[VI].