Journal Article

Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes

Stark, Jeremy, Derbes, Rebecca S., Ade, Catherine M., Deininger, Prescott L., Roy-Engel, Astrid M., Morales, Maria E., Ortego, Jonathan C.

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alu elements / Arsenic / Arsenic trioxide / Biology and Life Sciences / Cadmium / Cancer / Carcinogenesis / Carcinogens / Cell culture / Cell cycle / Cell Line, Tumor / Chromosome aberrations / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded - drug effects / DNA damage / DNA repair / DNA Repair - drug effects / Dose-Response Relationship, Drug / Drug resistance / Epidemiology / Exposure / Gene expression / Genes, Reporter - genetics / Genomes / Green Fluorescent Proteins - genetics / Hazardous materials / Hazardous substances / Health sciences / Heavy metals / Homologous recombination / Homology / Humans / Influence / Inhibition / Leukemia / Medicine and Health Sciences / Metal chlorides / Metals, Heavy - pharmacology / Mutation / Nickel / Nickel chloride / Nickel compounds / Non-homologous end joining / Physical Sciences / Proteins / Recombination, Genetic - drug effects / Repair