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Review
. 2020 Mar 16;33(3):709-726.
doi: 10.1021/acs.chemrestox.9b00464. Epub 2020 Feb 7.

Molecular Mechanisms of Arsenic-Induced Disruption of DNA Repair

Lok Ming Tam, Nathan E Price, Yinsheng Wang
Review

Molecular Mechanisms of Arsenic-Induced Disruption of DNA Repair

Lok Ming Tam et al. Chem Res Toxicol. .

Abstract

Exposure to arsenic in contaminated drinking water is an emerging public health problem that impacts more than 200 million people worldwide. Accumulating lines of evidence from epidemiological studies revealed that chronic exposure to arsenic can result in various human diseases including cancer, type 2 diabetes, and neurodegenerative disorders. Arsenic is also classified as a Group I human carcinogen. In this review, we survey extensively different modes of action for arsenic-induced carcinogenesis, with focus being placed on arsenic-mediated impairment of DNA repair pathways. Inorganic arsenic can be bioactivated by methylation, and the ensuing products are highly genotoxic. Bioactivation of arsenicals also elicits the production of reactive oxygen and nitrogen species (ROS and RNS), which can directly damage DNA and modify cysteine residues in proteins. Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Inorganic arsenic and its metabolism. In liver, absorbed As5+ is reduced to As3+ by GSH as an electron donor, and As3+ undergoes sequential methylation and reduction with SAM and GSH as the donors of methyl group and electron, respectively, to generate MMAV, MMAIII DMAV, and DMAIII.
Figure 2.
Figure 2.
iAs-elicited oxidative stress enhances carcinogenesis through impairing DNA repair pathway to induce mutations in DNA. As3+ can induce the overproduction of ROS and RNS through mitochondria dysfunction, cellular antioxidant imbalance, and impairment of ROS-scavenging enzymes. Hence, iAs-elicited oxidative stress induces oxidative DNA damage, disturbs PTMs of DNA repair enzymes, and disrupts protein tyrosine phosphorylation, thereby enhancing DNA mutations to promote carcinogenesis.
Figure 3.
Figure 3.
Major events governing the disruption of DNA repair pathways by iAs and its trivalent metabolites. Arsenite and its metabolites induce cell proliferation while inhibiting BER, NER, DSB repair, ICL repair, DDR signaling, cell cycle checkpoint regulation, and apoptosis of damaged cells. These together diminish the capacity of DNA repair and impair genetic integrity.
Figure 4.
Figure 4.
Modes of action of inorganic arsenic and iAs-induced ROS/RNS in impairing the enzymatic activity of zinc finger (ZnF) proteins. iAs and ROS/RNS can target vicinal cysteines within the zinc coordination spheres of zinc finger proteins: (i) As3+ directly binds to these cysteines more strongly than Zn2+; (ii) ROS oxidizes these cysteines to form a series of oxidization products, such as –SOH and –S–S–; (iii) RNS, especially peroxynitrite, can S-nitrosylate these cysteines. In all these cases, Zn2+ bound within zinc finger motifs is released through its displacement by As3+, which alters the conformation of zinc finger proteins and hence their enzymatic activities.
Figure 5.
Figure 5.
Major events through which inorganic arsenite and its trivalent metabolites disrupt epigenetic integrity via inhibition of epigenetic regulators and chromatin modifiers. As3+, MMAIII, and DMAIII can impair the enzymatic activities of DNA epigenetic regulators (e.g., DNMTs, Tet, and CTCF) and chromatin-modifying enzymes (e.g., hMOF, TIP60, and PARP1), which subsequently perturb DNA methylation and histone PTMs, respectively, thereby disrupting epigenetic integrity.
Figure 6.
Figure 6.
Arsenite disrupts DNA methylation. Methylation events in promoters repress gene expression, whereas those in gene bodies activate gene expression. Metabolism of iAs induces SAM deficiency, which results in global DNA hypomethylation. iAs exposure leads to decreased expressions of DNMT1, DNMT3A, DNMT3B, thus diminishing global DNA methylation. Additionally, iAs selectively inhibits the binding of CTCF to promoters of genes (e.g., DNMTs), leading to repression of tumor suppressor genes. Meanwhile, iAs inhibits Tet proteins, thus reducing the level of 5-hmC, which can be inhibited by weakened occupancy of CTCF in the promoters of TET genes. Combined together, iAs can repress tumor suppressors and activate proto-oncogenes, thereby impairing DNA repair and genome integrity.
Figure 7.
Figure 7.
Arsenite and iAs-induced oxidative stress enhance DNA damage through disrupting the functions of zinc finger proteins. iAs-induced oxidative stress and As3+ itself can disrupt the zinc finger-containing epigenetic regulators and DNA repair enzymes, thereby impairing DNA repair. Simultaneously, oxidative stress generates oxidative DNA damage. These together may result in tumorigenesis.
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