Impact of arsenic on nucleotide excision repair: XPC function, protein level, and gene expression

Abstract

The ubiquitous occurrence of the human carcinogen arsenic results in multiple exposure possibilities to humans. The human diet, especially drinking water, is the primary source of inorganic arsenic intake in the general population. The ingested arsenic is metabolized to methylated derivatives; some of these metabolites are today considered to be more toxic than the inorganic species. Various modes of action have been proposed to contribute to arsenic carcinogenicity; inhibition of nucleotide excision repair (NER), removing DNA helix distorting DNA adducts induced by environmental mutagens, is likely to be of primary importance. Here, we report that arsenite and its metabolite monomethylarsonous acid (MMA(III)) strongly decreased expression and protein level of Xeroderma pigmentosum complementation group C (XPC), which is believed to be the principle initiator of global genome NER. This led to diminished association of XPC to sites of local UVC damage, resulting in decreased recruitment of further NER proteins. Additionally Xeroderma pigmentosum complementation group E protein (XPE) expression was reduced, which encodes for another important NER protein and similarly to XPC is regulated by the activity of the transcription factor p53. In summary, our data demonstrate that in human skin fibroblasts arsenite and even more pronounced MMA(III) interact with XPC expression, resulting in decreased XPC protein level and diminished assembly of the NER machinery.

Inhibition of nucleotide excision repair by arsenic

“…DMA V , the only methylated metabolite of inorganic arsenic that has been studied in this respect did not change the expression of DNA repair genes, including XPB, of bladder transitional epithelium in F344 rats [52]. Most recently, Nollen et al [53] found that a 24-h treatment with arsenite or MMA III strongly decreased XPC at both the mRNA and protein levels in normal human skin fibroblasts immortalized by telomerase transfection (VH10hTert). The reduced level of XPC expression led to a diminished localization of XPC to UV-damaged spots in the nucleus.…”

Methylarsenic compounds [MAK Value Documentation, 2014]

“…Among the indirect genotoxic effects are also changes in the expression of genes of specific DNA repair proteins. Methylated arsenic compounds thus cause a reduction in xeroderma pigmentosum protein C (XPC) expression, which is a major damage recognition protein in nucleotide excision repair (Nollen et al 2008). …”

Mitigating cisplatin resistance in ovarian cancer.

“…XPC is actively involved in the recognition and initiation of cisplatin-DNA damage repair in GGR (Earley and Turchi, 2010;Neher, et aL, 2010). Arsenic has been shown to inhibit NER by inhibiting XPC expression (Nollen, et aL, 2009). In the current study, I observed that P53 and XPC were induced by cisplatin.…”

“…Mechanisms of arsenic induced cytotoxicity include: inhibition of nucleotide excision repair (Hartwig, et aL, 1997;Hartwig, et aL, 2003;Nollen, et aL, 2009;, causation of oxidative stress (Shi, et aL, 2004b;Shi, et aI., 2004a), induction of mitotic catastrophe (Taylor, et aL, 2008;McNeely, et aL, 2008a) and induction of apoptotic cell death (HU, et aL, 2005;Ramos, et aL, 2005). Resistance to arsenic is associated with enhanced metallothionein binding, detoxification by glutathione conjugation and efflux by multi-drug resistance proteins (Leslie, et aL, 2004), similar to cisplatin and its analogues (Cole, et aL, 1994;Byun, et aL, 2005;Surowiak, et aL, 2005).…”

“…Arsenic has additive or synergistic effect with cisplatin following prolonged exposure (Uslu, et aL, 2000;Wang, et aL, 2001;Zhang, et aL, 2009). Mechanisms of arsenic-induced cell death include formation of oxidative DNA damage (Nakagawa, et aL, 2002), activation of the Fas pathway (Kong, et aL, 2005), and inhibition of NER (Nollen, et aL, 2009;) and causation of mitotic catastrophe (McNeely, et aL, 2008a). …”