Identification and Characterization of Mutations in the Antioxidant Gene, Prdx1, from Qatari Population.

Abstract

Peroxiredoxin 1 (PRDX1) is a highly conserved antioxidant enzyme that plays a critical role in detoxifying peroxides and regulating redox homeostasis. Beyond its enzymatic activity, PRDX1 serves as a redox-sensitive modulator of key signaling pathways involved in apoptosis, DNA repair, and immune regulation. Its functional versatility has made it increasingly recognized in cancer biology, where it can act either as a tumor suppressor or a tumor promoter, depending on the cellular context. Loss of PRDX1 function has been linked to genomic instability, heightened inflammation, and increased susceptibility to oxidative damage⸻features commonly associated with cancer progression. We previously demonstrated that PRDX1-deficient cells are hypersensitive to sodium arsenite, a naturally occurring metalloid with established chemotherapeutic potential. This hypersensitivity suggests that PRDX1 plays a protective role against arsenite-induced oxidative stress and highlights its relevance as a potential biomarker for arsenite-based cancer therapy. Given this, our current study investigated whether naturally occurring PRDX1 variants found in the Qatari population alter cellular sensitivity to arsenite. Fifteen PRDX1 variants unique to the Qatari genome were assessed alongside four engineered mutants designed to disrupt critical functional regions of the protein. These variants were introduced into a cellular model to evaluate their ability to rescue or exacerbate arsenite-induced toxicity. Our findings revealed a spectrum of functional outcomes, ranging from complete loss of antioxidant protection to unexpected toxic effects that sensitized cells further to arsenite. Our results demonstrate the functional diversity of PRDX1 variants and reinforce its role as a modulator of oxidative stress responses. This study offers insight into population-specific genetic variation in PRDX1 and establishes a framework for using arsenite sensitivity as a tool to functionally characterize redox-regulating genes. It also provides a foundation for future work exploring PRDX1 as a biomarker for redox-based cancer therapies.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences