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
HERO ID
1015694
Reference Type
Journal Article
Year
2012
Language
English
PMID
| HERO ID | 1015694 |
|---|---|
| In Press | No |
| Year | 2012 |
| Title | Poly(ADP-ribose) polymerase-1 inhibition by arsenite promotes the survival of cells with unrepaired DNA lesions induced by UV exposure |
| Authors | Qin, X-J; Liu, W; Li, Y-N; Sun, X; Hai, C-X; Hudson, LG; Liu, KJ |
| Journal | Toxicological Sciences |
| Volume | 127 |
| Issue | 1 |
| Page Numbers | 120-129 |
| Abstract | 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. |
| Doi | 10.1093/toxsci/kfs099 |
| Pmid | 22387748 |
| Wosid | WOS:000303490100012 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | |WOS:000303490100012 |
| Is Public | Yes |
| Language Text | English |
| Keyword | arsenic; PARP-1; PARG; DNA damage repair; carcinogenesis |
| Is Qa | No |