Inhibition of nucleotide excision repair by arsenic

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.

Arsenic Binding to Proteins

“…115−117 These trivalent arsenicals were found to inhibit the activities of several DNA repair proteins, including poly(ADP-ribose) polymerase-1 (PARP-1), formamidopyrimidine-DNA glycosylase (Fpg), and xeroderma pigmentosum group A protein (XPA), each containing a zinc finger DNA binding domain. 118,119 The interactions between these repair proteins and arsenic compounds resulted in the release of zinc.…”

The crosstalk between trace elements with DNA damage response, repair, and oxidative stress in cancer

“…The possible mechanisms of NER inhibition by As include its effects on the expression of NER protein, the function of NER protein, the p53 phosphorylation, and p53 DNA‐binding activity, which could modulate NER via transcriptional activation of downstream NER genes . Several studies demonstrated that excision repair cross‐complementing proteins 1 and 2 (ERCC1 and ERCC2), as two of the key components of the NER pathway, are regulated by As .…”

“…255 The possible mechanisms of NER inhibition by As include its effects on the expression of NER protein, the function of NER protein, the p53 phosphorylation, and p53 DNA-binding activity, which could modulate NER via transcriptional activation of downstream NER genes. 256 Several studies demonstrated that excision repair crosscomplementing proteins 1 and 2 (ERCC1 and ERCC2), as two of the key components of the NER pathway, are regulated by As. 257,258 Exposure to As can decrease expression levels of Lig1 and Lig3 at both mRNA and protein levels in mammalian cells, expression levels of ERCC1, XPF, and XPB in lymphocytes, and expression of ERCC1 at both mRNA and protein levels in human and cultured cardiomyocytes.…”

Disruption of iron homeostasis and resultant health effects upon exposure to various environmental pollutants: A critical review

“…Emerging evidence suggests that inactivation of this enzyme causes the disruption of energy homeostasis (Shen et al, 2013a) and possibly iron homeostasis (Ye and Rouault, 2010). DNA repair enzymes that mediate nucleotide excision repair (NER) can also be inhibited by As through several pathways, including the induction of nitric oxide (NO) (Shen et al, 2013b). It is considered that NO interacts with the iron center of IRPs, and thus alters the ferritin and transferrin levels, resulting in enlarged cellular LIP (Verma et al, 2015).…”