Interactions with the DNA Damage Response System

Cadmium has been shown to impair almost all major DNA repair pathways. Convincing evidence is available for its interference with nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR) fi equently, effects were observed at comparatively low, non-cytotoxic concentrations (reviewed in [43 6]). Since DNA repair systems are not only requited for the repair of DNA damage induced by environmental, workplace and food mutagens, but also for the elimination of DNA lesions due to endogenous processes and to keep replication errors low, the disturbance of DNA repair processes may explain co-mutagenic 

One other DNA repair system of particular relevance for maintaining genomic stability is MMR. This evolutionary conserved pathway is responsible for the repair of mismatched normal bases after DNA replication, contributing significantly to the extraordinary fidelity of DNA replication. Cells deficient in MMR exert a mutator phenotype , in which the rate of spontaneous mutations is greatly elevated, and defects in MMR are associated with an increased risk of different types of cancer. 

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Cadmium salts do not cause DNA damage in cell extracts or with isolated DNA [14] but rather interact with proteins therefore, the genotoxicity of cadmium is likely due to indirect mechanisms. Predominantly the induction of oxidative stress and interactions with the DNA damage response systems may be relevant in cadmium-induced genotoxicity. 

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