Differential sensitivities of cellular XPA and PARP-1 to arsenite inhibition and zinc rescue

Journal Article · Fri Sep 15 04:00:00 EDT 2017 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2017.05.031· OSTI ID:22722926

Ding, Xiaofeng ^[1]; Zhou, Xixi; Cooper, Karen L.; Huestis, Juliana ^[1]; Liu, Ke Jian ^[1]

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1. Department of Pharmaceutical Sciences, College of Pharmacy, The University of New Mexico, Albuquerque, NM 87131 (United States)

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. - Highlights: • Arsenite suppresses the chromatin binding activity of XPA and PARP-1. • Arsenite has greater effect on retention of direct DNA damage such as CPDs and 6.4-PPs. • Arsenite inhibits DNA repair through both BER and NER pathways.

• OSTI ID: 22722926
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 331; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CHROMATIN
DNA DAMAGES
EXCISION REPAIR
INHIBITION
PYRIMIDINE DIMERS
SENSITIVITY
ULTRAVIOLET RADIATION
ZINC