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ATM And MRE11 Are Involved In The Repair Of Particulate Chromium (VI) -Induced Dna Double Strand Breaks
Xie, H; Dako, S; Wise, SS; Katsifis, SP; Wise, JP
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Chromium(VI) (Cr(VI)) is a potent respiratory toxicant and carcinogen with widespread human exposure. The most toxic and carcinogenic forms of Cr(VI) are particulates such as lead chromate (LC), which deposit and persist in the respiratory tract after inhalation. Lead chromate particles are genotoxic to cultured fibroblasts and epithelia. The particle-derived Cr(VI) ion enters the cell where it undergoes a uniquely complex scheme of reductive metabolism, producing a cascade of reactive intermediates which produce numerous types of DNA damage. Our previous study linked lead chromate to DNA double strand breaks (DSBs) formation, one of the most dangerous types of DNA damage. Thus the aim of this study was to understand the mechanisms of repair of lead chromate-induced DNA DSBs. Using the comet assay, we found that LC induced concentration dependent increases in DSBs in normal human lung cells with 0.1, 0.5, 1, and 5 ug/cm2 LC inducing 14, 24, 32 and 37 percent relative increase in tail DNA relative to control, respectively. We found that repair of these lesions occurred within 24 h. In response to DNA damage, cells arrest the cell cycle to facilitate repair or initiate apoptosis. We found that LC caused S-phase arrest and increased levels of phosphorylated SMC1 expression. LC also induced ATM and MRE11 expression in these cells. To begin understanding the mechanism of repair for these lesions, we treated ATM deficient and MRE11 deficient cells with LC. We found that LC induces DSBs in ATM deficient cells and MRE11 deficient cells and the repair of these lesions is greatly decreased. Using an immunofluorescence assay we found that MRE11 and H2A.X foci co-localize after LC exposure. These data indicate that MRE11 and ATM are involved in LC-induced DSBs sensing and repair.
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