Attenuation of DNA damage-induced p53 expression by arsenic: a possible mechanism for arsenic co-carcinogenesis.
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.
Shen
Shengwen
S
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Lee
Jane
J
Weinfeld
Michael
M
Le
X Chris
XC
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001151:Arsenic / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003043:Cocarcinogenesis; D018736:DNA Adducts / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D000071456:Sequestosome-1 Protein; D051758:Transcription Factor TFIIH / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C117669:DDB2 protein, human; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D009942:Organometallic Compounds; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D016159:Tumor Suppressor Protein p53; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; C406082:monomethylarsonous acid; D051758:Transcription Factor TFIIH; C086984:XPC protein, human; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D001151:Arsenic