Abstract
Inhibition of DNA repair is one proposed mechanism for the co-mutagenicity/co-carcinogenicity of arsenic. This review summarizes the current literature on the effects of arsenic compounds on nucleotide excision repair (NER). Several possible mechanisms for the observed NER inhibition have been proposed. Modulation of the expression of NER proteins has been considered to be one possibility of impairing the NER process. However, data on the effects of arsenic on the expression of NER proteins remain inconsistent. It is more likely that arsenic inhibits the induction of accessory or other key proteins involved in cellular control of DNA repair pathways, such as p53. For example, arsenic affects p53 phosphorylation and p53 DNA binding activity, which could regulate NER through transcriptional activation of downstream NER genes. Although it is important to study possible direct inactivation of NER proteins by arsenic binding, indirect inactivation of proteins having thiol residues critical to their function or zinc finger proteins cannot be negated. For example, nitric oxide (NO) induced in arsenic-treated cells serves as a specific inhibitor of NER, possibly through NO-induced S-nitrosylation of proteins related to DNA repair. Poly(ADP-ribose) polymerase-1, a zinc finger protein implicated in both NER and base excision repair (BER), deserves special attention because of its involvement in NO production and its broad range of protein substrates including many repair enzymes.
Highlights
1.1 Arsenic and its co-carcinogenicityInorganic arsenic is a ubiquitous environmental contaminant that has long been classified as a human carcinogen but its carcinogenic effects have not been conclusively demonstrated in laboratory animals [1,2,3]
This review summarizes the current literature on the effects of arsenic compounds on nucleotide excision repair (NER)
Nitric oxide (NO) induced in arsenic-treated cells serves as a specific inhibitor of NER, possibly through nitric oxide (NO)-induced S-nitrosylation of proteins related to DNA repair
Summary
Inorganic arsenic (arsenite and arsenate) is a ubiquitous environmental contaminant that has long been classified as a human carcinogen but its carcinogenic effects have not been conclusively demonstrated in laboratory animals [1,2,3]. It is reasonable to consider that arsenic acts as a co-carcinogen, some arsenic compounds have been shown to act as complete carcinogens in a few animal models [1]. This co-mutagenicity/co-carcinogenicity of arsenic might explain the lack of tumor development in most laboratory animals challenged with inorganic arsenic alone and the relative ease with which tumors were initiated when arsenic compounds were administered before, during, or after exposure to a potent carcinogen (an initiator). Co-exposure to cigarette smoking and arsenic has been shown to be linked to elevated rates of lung cancer in several epidemiological studies [8]
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