Enhanced glutathione levels confer resistance to apoptotic and ferroptotic programmed cell death in NEIL DNA glycosylase deficient HAP1 cells

• Published in: Free radical biology & medicine Vol. 213; pp. 470 - 487
• Main Authors: Neurauter, Christine Gran, Pannone, Marco, Sousa, Mirta Mittelstedt Leal de, Wang, Wei, Kuśnierczyk, Anna, Luna, Luisa, Sætrom, Pål, Scheffler, Katja, Bjørås, Magnar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2024
• Subjects: Apoptosis; Ferroptosis; Glutathione; NEIL DNA glycosylases; Oxidative stress resistance; Ferroptosis; NEIL DNA glycosylases; Oxidative stress resistance; Glutathione; Apoptosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2024.01.037

The NTHL1 and NEIL1-3 DNA glycosylases are major enzymes in the removal of oxidative DNA base lesions, via the base excision repair (BER) pathway. It is expected that lack of these DNA glycosylases activities would render cells vulnerable to oxidative stress, promoting cell death. Intriguingly, we found that single, double, triple, and quadruple DNA glycosylase knockout HAP1 cells are, however, more resistant to oxidative stress caused by genotoxic agents than wild type cells. Furthermore, glutathione depletion in NEIL deficient cells further enhances resistance to cell death induced via apoptosis and ferroptosis. Finally, we observed higher basal level of glutathione and differential expression of NRF2-regulated genes associated with glutathione homeostasis in the NEIL triple KO cells. We propose that lack of NEIL DNA glycosylases causes aberrant transcription and subsequent errors in protein synthesis. This leads to increased endoplasmic reticulum stress and proteotoxic stress. To counteract the elevated intracellular stress, an adaptive response mediated by increased glutathione basal levels, rises in these cells. This study reveals an unforeseen role of NEIL glycosylases in regulation of resistance to oxidative stress, suggesting that modulation of NEIL glycosylase activities is a potential approach to improve the efficacy of e.g. anti-inflammatory therapies. [Display omitted] •Lack of NEIL DNA glycosylases induces resistance to oxidative stress in HAP1 cells.•Inhibition of Glutathione synthesis further enhances resistance to oxidative stress in NEIL KO.•NEIL deficiency leads to an adaptive response via regulation of glutathione levels.•NEIL deficiency prevents cell death triggered via both apoptosis and ferroptosis.•Modulation of NEIL activities holds potential for the treatment of human diseases.