Mft1, Identified from a Genome-wide Screen of the Yeast Haploid Mutants, Mediates Cell Cycle Arrest to Counteract Quinoxaline-induced Toxicity

Overview

Journal Front Genet

Date 2024 Jan 29

PMID 38283148

Authors

Abdallah Alhaj Sulaiman

Dana E Al-Ansari

Reem Ali

Mustapha Aouida

Dindial Ramotar

Affiliations

Soon will be listed here.

Abstract

Quinoxaline is a heterocyclic compound with a two-membered ring structure that undergoes redox cycling to produce toxic free radicals. It has antiviral, antibacterial, antifungal, and antitumor activities. However, the biological functions that are involved in mounting a response against the toxic effects of quinoxaline have not been investigated. Herein, we performed a genome-wide screen using the yeast haploid mutant collection and reported the identification of 12 mutants that displayed varying sensitivity towards quinoxaline. No mutant was recovered that showed resistance to quinoxaline. The quinoxaline-sensitive mutants were deleted for genes that encode cell cycle function, as well as genes that belong to other physiological pathways such as the vacuolar detoxification process. Three of the highly sensitive gene-deletion mutants lack the , , and genes. While Ddc1 and Dun1 are known to perform roles in the cell cycle arrest pathway, the role of Mft1 remains unclear. We show that the mutant is as sensitive to quinoxaline as the mutant. However, the double mutant lacking the and genes, is extremely sensitive to quinoxaline, as compared to the and single mutants. We further show that the mutant is unable to arrest in the G2/M phase in response to the drug. We conclude that Mft1 performs a unique function independent of Ddc1 in the cell cycle arrest pathway in response to quinoxaline exposure. This is the first demonstration that quinoxaline exerts its toxic effect likely by inducing oxidative DNA damage causing cell cycle arrest. We suggest that clinical applications of quinoxaline and its derivatives should entail targeting cancer cells with defective cell cycle arrest.

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