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1015694 
Journal Article 
Poly(ADP-ribose) polymerase-1 inhibition by arsenite promotes the survival of cells with unrepaired DNA lesions induced by UV exposure 
Qin, X-J; Liu, W; Li, Y-N; Sun, X; Hai, C-X; Hudson, LG; Liu, KJ 
In Press 
Yes 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
127 
120-129 
English 
Human arsenic exposure is associated with increased risk of skin cancer and arsenite greatly enhances ultraviolet (UV)-induced skin tumors in a mouse model of carcinogenesis. Inhibition of DNA repair is one proposed mechanism for the observed co-carcinogenicity. We have previously demonstrated that low concentrations of arsenite inhibit Poly (ADP-ribose) polymerase (PARP)-1, thus interfering with DNA-repair process triggered by UV radiation. Since over-activation of PARP-1 often leads to apoptotic cell death, and unrepaired DNA lesions promote genomic instability and carcinogenesis, we hypothesized that inhibition of PARP-1 by arsenic may promote the survival of potentially "initiated carcinogenic cells", i.e., cells with unrepaired DNA lesions. In the present study, we tested this hypothesis on UV-challenged HaCat cells. Cells were pretreated with 2 μM arsenite for 24 hrs before UV exposure. Outcome parameters included apoptotic death rate, PARP-1 activation, apoptotic molecules and retention of DNA lesions. UV exposure induced PARP-1 activation and associated PAR production, apoptosis inducing factor (AIF) release, cytochrome C release and caspases activation, which led to apoptotic death in HaCat cells. Pretreatment with 2 μM arsenite significantly inhibited UV-induced cell death as well as the associated molecular events. Notably, knockdown of PARP-1 with siRNA completely abolished the antagonism of arsenite. Furthermore, arsenite pretreatment led to long-term retention of UV-induced cyclobutane-pyrimidine dimers (CDPs). Together, these results suggest that low concentration of arsenite reduces UV-induced apoptosis via inhibiting PARP-1, thus promoting the survival of cells with unrepaired DNA lesions, which may be an important mechanism underlying arsenic co-carcinogenic action. 
arsenic; PARP-1; PARG; DNA damage repair; carcinogenesis 
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