Attenuation of DNA damage‐induced p53 expression by arsenic: A possible mechanism for arsenic co‐carcinogenesis

Abstract

Inhibition of DNA repair processes has been suggested as one predominant mechanism in arsenic co-genotoxicity. However, the underlying mode of action responsible for DNA repair inhibition by arsenic remains elusive. To further elucidate the mechanism of repair inhibition by arsenic, we examined the effect of trivalent inorganic and methylated arsenic metabolites on the repair of benzo(a)pyrene diol epoxide (BPDE)-DNA adducts in normal human primary fibroblasts and their effect on repair-related protein expression. We observed that monomethylarsonous acid (MMA(III)) was the most potent inhibitor of the DNA repair. MMA(III) did not change the expression levels of some key repair proteins involved upstream of the dual incision in the global nucleotide excision repair (NER) pathway, including p48, XPC, xeroderma pigmentosum complementation group A (XPA), and p62-TFIIH. However, it led to a marked impairment of p53 induction in response to BPDE treatment. The abrogated p53 expression translated into reduced p53 DNA-binding activity, suggesting a possibility of downregulating downstream repair genes by p53. A p53-null cell line failed to exhibit the inhibitory effect of MMA(III) on NER, implicating a role for p53 in the NER inhibition by MMA(III). Further investigation revealed that MMA(III) dramatically inhibited p53 phosphorylation at serine 15, implying that MMA(III) destabilized p53 by inhibiting its phosphorylation. Because p53 is required for proficient global NER, our data suggest that arsenic inhibits NER through suppressing p53 induction in response to DNA damage in cells with normal p53 gene expression.

Interactions by Carcinogenic Metal Compounds with DNA Repair Processes

“…These data demonstrate that in human skin fibroblasts arsenite and MMA(III) more interacts with XPC expression, resulting in decreased XPC protein level and diminished assembly of the NER. The observed stronger impact on XPC by MMA(III) may explain the more potent NER inhibition by MMA(III) as compared to arsenite Shen et al, 2008). Finally, these data provide further evidence that in the case of DNA repair inhibition the biomethylation of arsenic increases inorganic arsenic induced genotoxicity and probably contributes to its carcinogenicity.…”

“…Since bulky lesion formation is the possible responsible for their carcinogenicity, genetic integrity depends largely on NER efficiency. Many studies have shown that inorganic arsenic inhibits repair of bulky DNA adducts induced by UV-irradiation Danaee et al, 2004) or benzo [a]pyrene in cultured cells and laboratory animals Shen et al, 2008); additionally arsenite has been shown to downregulate expression of some NER genes in cultured human cells (Hamadeh et al, 2005). In humans, arsenic exposure via drinking water was correlated with a dose relationship dependent to decreased expression of some NER genes and reduced repair of lesions in lymphocytes (Andrew et al, 2006).…”

Inhibition of nucleotide excision repair by arsenic

“…Furthermore, arsenic reduced unscheduled DNA synthesis (UDS) and the excision of CPDs irradiation. The reported studies of NER inhibition by arsenic [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] are summarized in Supporting Information Table S1.…”

Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells

“…These results differ from those reported by Simoes et al (35) in which no significant difference in p53 expression was found in p53-WT HCT 116 cells after a 24-h exposure to AA (100 μM). Many studies have showed that TP53 is involved in the nucleotide excision repair pathway and that loss of TP53 will enhance DNA damage (48)(49)(50). Shen et al (50) showed that arsenic can cause genotoxicity by inhibiting the p53-medicated nucleotide excision repair.…”

“…Many studies have showed that TP53 is involved in the nucleotide excision repair pathway and that loss of TP53 will enhance DNA damage (48)(49)(50). Shen et al (50) showed that arsenic can cause genotoxicity by inhibiting the p53-medicated nucleotide excision repair. Tsai et al (49) showed that arecoline, which is a major alkaloid of areca nut, can repress p53-activated DNA repair and induce DNA damage in human epithelial cells.…”