Oxidative damage induced genotoxic effects in human fibroblasts from Xeroderma Pigmentosum group A patients.

Abstract

Xeroderma Pigmentosum A protein plays a pivotal role in the nucleotide excision repair pathway. Through site-directed binding of rigidly kinked double-stranded DNA, it verifies damaged DNA for subsequent excision and incision. Although Xeroderma Pigmentosum A-deficient cells have shown to be defective in oxidative base-lesion repair, the effects of oxidative assault on such cells have not been fully explored. Therefore, we sought to determine the involvement of Xeroderma Pigmentosum A in oxidative DNA damage-repair by treating primary fibroblasts from a patient suffering from Xeroderma Pigmentosum A with sodium arsenite and hydrogen peroxide. Our results show dose-dependent increase in genotoxicity with little change in cytotoxicity with both arsenite and H2O2 in Xeroderma Pigmentosum A-deficient cells compared to control cells. Xeroderma Pigmentosum A-deficient cells displayed increased susceptibility and reduced repair capacity when subjected to DNA damage induced by oxidative stress. Superarray results of apoptotic genes revealed differential expression of approximately 10 genes between Xeroderma Pigmentosum A-deficient and normal cells following arsenite treatment. Interestingly, we noted that arsenite did not inflict as much damage in the cells compared to H2O2. Lack of functional Xeroderma Pigmentosum A seems to increase the susceptibility of oxidative stress-induced genotoxicity while retaining cell viability posing as a potential cancer risk factor of Xeroderma Pigmentosum A patients.

• Authors: Grace Kah Mun Low, Edwin Dan Zhihao Fok, Aloysius Poh Leong Ting, M Prakash Hande
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 40 Issue 11 Pg. 2583-95 ( 2008) ISSN: 1357-2725 [Print] Netherlands
• PMID: 18585952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arsenites
• Enzyme Inhibitors
• Oxidants
• Sodium Compounds
• Xeroderma Pigmentosum Group A Protein
• sodium arsenite
• Hydrogen Peroxide

Topics

• Arsenites (pharmacology)
• Cell Cycle (physiology)
• Cell Survival
• Cells, Cultured
• Chromosome Aberrations
• DNA Damage
• DNA Repair
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (cytology, drug effects, physiology)
• Gene Expression Profiling
• Humans
• Hydrogen Peroxide (metabolism)
• In Situ Hybridization, Fluorescence
• Oligonucleotide Array Sequence Analysis
• Oxidants (metabolism)
• Oxidative Stress
• Sodium Compounds (pharmacology)
• Xeroderma Pigmentosum Group A Protein (genetics, metabolism)