title: Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes.
abstract: Heavy metals such as cadmium, arsenic and nickel are classified as carcinogens. Although the precise mechanism of carcinogenesis is undefined, heavy metal exposure can contribute to genetic damage by inducing double strand breaks (DSBs) as well as inhibiting critical proteins from different DNA repair pathways. Here we take advantage of two previously published culture assay systems developed to address mechanistic aspects of DNA repair to evaluate the effects of heavy metal exposures on competing DNA repair outcomes. Our results demonstrate that exposure to heavy metals significantly alters how cells repair double strand breaks. The effects observed are both specific to the particular metal and dose dependent. Low doses of NiCl2 favored resolution of DSBs through homologous recombination (HR) and single strand annealing (SSA), which were inhibited by higher NiCl2 doses. In contrast, cells exposed to arsenic trioxide preferentially repaired using the "error prone" non-homologous end joining (alt-NHEJ) while inhibiting repair by HR. In addition, we determined that low doses of nickel and cadmium contributed to an increase in mutagenic recombination-mediated by Alu elements, the most numerous family of repetitive elements in humans. Sequence verification confirmed that the majority of the genetic deletions were the result of Alu-mediated non-allelic recombination events that predominantly arose from repair by SSA. All heavy metals showed a shift in the outcomes of alt-NHEJ repair with a significant increase of non-templated sequence insertions at the DSB repair site. Our data suggest that exposure to heavy metals will alter the choice of DNA repair pathway changing the genetic outcome of DSBs repair.
authors.affiliation: Department of Epidemiology and Tulane Cancer Center, and Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, United States of America.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Morales
authors.affiliation: Department of Epidemiology and Tulane Cancer Center, and Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, United States of America.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Derbes
authors.affiliation: Department of Cellular and Molecular Biology, Tulane University, 6400 Freret Street, New Orleans, LA 70118, United States of America.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Ade
authors.affiliation: Department of Epidemiology and Tulane Cancer Center, and Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, United States of America.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Ortego
authors.affiliation: Department of Radiation Biology, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd., Duarte, CA 91010, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stark
authors.affiliation: Department of Epidemiology and Tulane Cancer Center, and Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, United States of America.
authors.forename: Prescott L
authors.initials: PL
authors.lastname: Deininger
authors.affiliation: Department of Epidemiology and Tulane Cancer Center, and Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112, United States of America.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Roy-Engel
mesh_terms: D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D019216:Metals, Heavy / Q000494:pharmacology*; D011995:Recombination, Genetic / Q000187:drug effects
chemical_list: D019216:Metals, Heavy; D049452:Green Fluorescent Proteins