Molecular Mechanisms of Arsenic-Induced Disruption of DNA Repair

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 As 3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair.

Dynamic alteration in miRNA and mRNA expression profiles at different stages of chronic arsenic exposure-induced carcinogenesis in a human cell culture model of skin cancer

“…4). This observation is consistent with the widely accepted hypothesis that cell cycle dysregulation is an early event in arsenic-induced carcinogenesis (Al-Eryani et al 2017 ; Hunt et al 2014 ; States 2015 ; Tam et al 2020 ; Zhou and Xi 2018 ). Interestingly, the nucleotide excision repair (NER) pathway is induced at 7-wk (Fig.…”

“…1 ) in agreement with data from other groups (Pi et al 2008 ; Sun et al 2009 ). The slower growth rates in As 3+ exposed cells at early stages of exposure could reflect the well-characterized cell cycle arrest/delay effects of As 3+ exposure (Al-Eryani et al 2017 ; States 2015 ; States et al 2002 ; Tam et al 2020 ). This inference is supported by the pathway analysis which shows a multitude of cell cycle related pathways being dysregulated at 7-wk (Fig.…”

Complex Mechanisms of Antimony Genotoxicity in Budding Yeast Involves Replication and Topoisomerase I-Associated DNA Lesions, Telomere Dysfunction and Inhibition of DNA Repair

“…Inhibition of DNA repair is a well-established mechanism of As(III) genotoxicity, which involves downregulation of the DNA repair gene expression, disrupting catalytic activity and post-translational modifications of DNA repair proteins as well as their recruitment to the sites of DNA damage [ 127 , 134 ]. There are also a few reports indicating Sb(III) interference with DNA repair pathways [ 27 , 47 , 48 ].…”

QTMP, a Novel Thiourea Polymer, Causes DNA Damage to Exert Anticancer Activity and Overcome Multidrug Resistance in Colorectal Cancer Cells

“…The overaccumulation of ROS and RNS creates oxidative and nitrosative stress and plays important roles in regulating cell survival and death (36,37). As shown in Figures 6A and S6, QTMP induced ROS generation in a concentration-dependent manner, as indicated by a rightward shift in fluorescence in the FACS plots in SW480, HCT116 and Caco2 cells.…”