Cadmium inhibits non-homologous end-joining and over-activates the MRE11-dependent repair pathway.
Although cadmium still represents a public health problem and despite the fact that it has been classified as an IARC Group-I carcinogen, the molecular and cellular mechanisms responsible for the toxicity and the carcinogenicity of cadmium compounds are poorly known. Since unrepaired DNA double-strand breaks (DSBs) are considered to be key-lesions in cell lethality, and because misrepaired DSBs are a source of genomic instability leading to cancer proneness, the activity of the major DSB-repair pathways, i.e. non-homologous end-joining (NHEJ) and recombination, has been evaluated in human endothelial cells exposed to cadmium chloride and cadmium diacetate. Exposure to cadmium results in the production of DSBs a few hours after incubation. These breaks trigger the phosphorylation of H2AX proteins, which was used as an indirect measure of DSB in this study. The presence of cadmium in cells decreases the repair rate of X-ray-induced DSBs, suggesting an impact of cadmium upon the reparability of DSBs. Such an interpretation was consolidated by the finding that the DNA-PK kinase activity, essential for NHEJ, is affected by the presence of cadmium. These results suggest that the toxicity of cadmium compounds may be explained by the propagation of persistent DSBs. In parallel, the presence of cadmium was also associated with an over-activation of the MRE11-dependent repair pathway that may favour genomic instability. Altogether, our data provide a first example of the impact of cadmium upon DSB repair and signalling.
INSERM U836, ID17, European Synchrotron Radiation Facility, Rue Horowitz, 38043 Grenoble, France.
Muriel
M
Viau
Jérôme
J
Gastaldo
Zuzana
Z
Bencokova
Aurélie
A
Joubert
Nicolas
N
Foray
D019256:Cadmium Chloride / Q000633:toxicity*; D002460:Cell Line; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism; D006801:Humans; D000076228:MRE11 Homologue Protein; D010766:Phosphorylation; D011995:Recombination, Genetic / Q000187:drug effects*; D014965:X-Rays
D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C121766:MRE11 protein, human; D051747:DNA-Activated Protein Kinase; D000076228:MRE11 Homologue Protein; D004265:DNA Helicases; D019256:Cadmium Chloride