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Lack of superoxide dismutase in a rad51 mutant exacerbates genomic instability and oxidative stress‐mediated cytotoxicity in Saccharomyces cerevisiae

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&NA; A genetic analysis of synthetic lethal interactions in yeast revealed that the mutation of SOD1, encoding an antioxidant enzyme that scavenges superoxide anion radical, impaired the growth of a… Click to show full abstract

&NA; A genetic analysis of synthetic lethal interactions in yeast revealed that the mutation of SOD1, encoding an antioxidant enzyme that scavenges superoxide anion radical, impaired the growth of a set of mutants defective in homologous recombination (HR) pathway. Hence, SOD1 inhibition has been proposed as a promising approach for the selective killing of HR‐deficient cancer cells. However, we show that the deletion of RAD51 and SOD1 is not synthetic lethal but displays considerably slow growth and synergistic sensitivity to both reactive oxygen species (ROS)‐ and DNA double‐strand break (DSB)‐generating drugs in the budding yeast Saccharomyces cerevisiae. The function of Sod1 in regard to Rad51 is dependent on Ccs1, a copper chaperone for Sod1. Sod1 deficiency aggravates genomic instability in conjunction with the absence of Rad51 by inducing DSBs and an elevated mutation frequency. Inversely, lack of Rad51 causes a Sod1 deficiency‐derived increase of intracellular ROS levels. Taken together, our results indicate that there is a significant and specific crosstalk between two major cellular damage response pathways, ROS signaling and DSB repair, for cell survival. Graphical abstract Figure. No caption available. HighlightsSOD1 inhibition can be used for selective killing of cancer cells deficient in homologous recombination pathway.Deletion of RAD51 and SOD1 does not show synthetic lethality in budding yeast.Sod1 deficiency aggravates genomic instability in conjunction with the absence of Rad51.Accumulation of Rad51 deficiency‐mediated DSB lesions increases intracellular ROS levels in the absence of Sod1.DSB repair pathways and ROS response signaling have significant mutual genetic crosstalk.

Keywords: genomic instability; saccharomyces cerevisiae; sod1; deficiency; rad51

Journal Title: Free Radical Biology and Medicine
Year Published: 2018

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