Deficient repair of particulate hexavalent chromium-induced DNA double strand breaks leads to neoplastic transformation.
Hexavalent chromium (Cr(VI)) is a potent respiratory toxicant and carcinogen. The most carcinogenic forms of Cr(VI) are the particulate salts such as lead chromate, which deposit and persist in the respiratory tract after inhalation. We demonstrate here that particulate chromate induces DNA double strand breaks in human lung cells with 0.1, 0.5, and 1 microg/cm(2) lead chromate inducing 1.5, 2, and 5 relative increases in the percent of DNA in the comet tail, respectively. These lesions are repaired within 24 h and require Mre11 expression for their repair. Particulate chromate also caused Mre11 to co-localize with gamma-H2A.X and ATM. Failure to repair these breaks with Mre11-induced neoplastic transformation including loss of cell contact inhibition and anchorage-independent growth. A 5-day exposure to lead chromate induced loss of cell contact inhibition in a concentration-dependent manner with 0, 0.1, 0.5, and 1 microg/cm(2) lead chromate inducing 1, 78, and 103 foci in 20 dishes, respectively. These data indicate that Mre11 is critical to repairing particulate Cr(VI)-induced double strand breaks and preventing Cr(VI)-induced neoplastic transformation.
Xie
Hong
H
Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, University of Southern Maine, Portland, ME 04104-9300, USA.
Wise
Sandra S
SS
Wise
John P
JP
D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology*; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D000076228:MRE11 Homologue Protein; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D002857:Chromium; C074702:chromium hexavalent ion; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein