Oxidative damage induced genotoxic effects in human fibroblasts from Xeroderma Pigmentosum group A patients.
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.
Low
Grace Kah Mun
GK
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9, 2 Medical Drive, Singapore 117597, Singapore.
Fok
Edwin Dan Zhihao
ED
Ting
Aloysius Poh Leong
AP
Hande
M Prakash
MP
D018053:Arsenites / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D017670:Sodium Compounds / Q000494:pharmacology; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics* / Q000378:metabolism
D018053:Arsenites; D004791:Enzyme Inhibitors; D016877:Oxidants; D017670:Sodium Compounds; D051760:Xeroderma Pigmentosum Group A Protein; C017947:sodium arsenite; D006861:Hydrogen Peroxide