Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three of the most plausible biological theories of arsenic carcinogenesis are protein binding, oxidative stress and altered DNA methylation. This review presents the role of trivalent arsenicals binding to proteins in arsenic carcinogenesis. Using vacuum filtration based receptor dissociation binding techniques, the lifetimes of unidentate (<1s), bidentate (1-2min) and tridentate (1-2h) arsenite containing peptide binding complexes were estimated. According to our experimental data some of the protein targets to which arsenite may bind in vivo include tubulin, poly(ADP-ribose)polymerase (PARP-1), thioredoxin reductase, estrogen receptor-alpha, arsenic(+3)methyltransferase and Keap-1. Arsenite binding to tubulin can lead to several of the genetic effects observed after arsenic exposures (aneuploidy, polyploidy and mitotic arrests). Among many other possible arsenite binding sites are rat hemoglobin, the DNA repair enzyme xeroderma pigmentosum protein A (XPA), and other C2H2, C3H and C4 zinc finger proteins including members of the steroid receptor superfamily (e.g. glucocorticoid receptor). Macromolecules to which arsenite does not bind to include calf thymus DNA, mixed Type II-A histones and bovine H3/H4 histone. Although all six tested arsenicals released iron from ferritin, radioactive arsenite did not bind to the protein horse ferritin.
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PMID:The role of protein binding of trivalent arsenicals in arsenic carcinogenesis and toxicity. 1816 70

Arsenite directly binds to the zinc finger domains of the DNA repair protein poly (ADP ribose) polymerase (PARP)-1, and inhibits PARP-1 activity in the base excision repair (BER) pathway. PARP inhibition by arsenite enhances ultraviolet radiation (UVR)-induced DNA damage in keratinocytes, and the increase in DNA damage is reduced by zinc supplementation. However, little is known about the effects of arsenite and zinc on the zinc finger nucleotide excision repair (NER) protein xeroderma pigmentosum group A (XPA). In this study, we investigated the difference in response to arsenite exposure between XPA and PARP-1, and the differential effectiveness of zinc supplementation in restoring protein DNA binding and DNA damage repair. Arsenite targeted both XPA and PARP-1 in human keratinocytes, resulting in zinc loss from each protein and a pronounced decrease in XPA and PARP-1 binding to chromatin as demonstrated by Chip-on-Western assays. Zinc effectively restored DNA binding of PARP-1 and XPA to chromatin when zinc concentrations were equal to those of arsenite. In contrast, zinc was more effective in rescuing arsenite-augmented direct UVR-induced DNA damage than oxidative DNA damage. Taken together, our findings indicate that arsenite interferes with PARP-1 and XPA binding to chromatin, and that zinc supplementation fully restores DNA binding activity to both proteins in the cellular context. Interestingly, rescue of arsenite-inhibited DNA damage repair by supplemental zinc was more sensitive for DNA damage repaired by the XPA-associated NER pathway than for the PARP-1-dependent BER pathway. This study expands our understanding of arsenite's role in DNA repair inhibition and co-carcinogenesis.
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PMID:Differential sensitivities of cellular XPA and PARP-1 to arsenite inhibition and zinc rescue. 2855 76