Role of Xeroderma pigmentosum D (XPD) protein in genome maintenance in human cells under oxidative stress.

Abstract

Xeroderma pigmentosum D (XPD) protein plays a pivotal role in the nucleotide excision repair pathway. XPD unwinds the local area of the damaged DNA by virtue of constituting transcription factor II H (TFIIH) and is important not only for repair but also for basal transcription. Although cells deficient in XPD have shown to be defective in oxidative base-lesion repair, the effects of the oxidative assault on primary fibroblasts from patients suffering from Xeroderma Pigmentosum D have not been fully explored. Therefore, we sought to investigate the role of XPD in oxidative DNA damage-repair by treating primary fibroblasts derived from a patient suffering from Xeroderma Pigmentosum D, with hydrogen peroxide. Our results show dose-dependent increase in genotoxicity with minimal effect on cytotoxicity with H2O2 in XPD deficient cells compared to control cells. XPD deficient cells displayed increased susceptibility and reduced repair capacity when subjected to DNA damage induced by oxidative stress. XPD deficient fibroblasts exhibited increased telomeric loss after H2O2 treatment. In addition, we demonstrated that chronic oxidative stress induced accelerated premature senescence characteristics. Gene expression profiling revealed alterations in genes involved in transcription and nucleotide metabolisms, as well as in cellular and cell cycle processes in a more significant way than in other pathways. This study highlights the role of XPD in the repair of oxidative stress and telomere maintenance. Lack of functional XPD seems to increase the susceptibility of oxidative stress-induced genotoxicity while retaining cell viability posing as a potential cancer risk factor of Xeroderma Pigmentosum D patients.

• Authors: Grace Kah Mun Low, Aloysius Poh Leong Ting, Edwin Dan Zhihao Fok, Kalpana Gopalakrishnan, Dimphy Zeegers, Aik Kia Khaw, Manikandan Jayapal, Wilner Martinez-Lopez, M Prakash Hande
• Journal: Mutation research. Genetic toxicology and environmental mutagenesis (Mutat Res Genet Toxicol Environ Mutagen) 2022 Apr-May Vol. 876-877 Pg. 503444 ISSN: 1879-3592 [Electronic] Netherlands
• PMID: 35483790 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Hydrogen Peroxide
• Xeroderma Pigmentosum Group D Protein

Topics

• DNA Repair
• Humans
• Hydrogen Peroxide (toxicity)
• Oxidative Stress
• Xeroderma Pigmentosum (genetics)
• Xeroderma Pigmentosum Group D Protein (genetics, metabolism)