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Lack of superoxide dismutase in a rad51 mutant exacerbates genomic instability and oxidative stress-mediated cytotoxicity in Saccharomyces cerevisiae.
Free Radic Biol Med. 2018 12; 129:97-106.FR

Abstract

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.

Authors+Show Affiliations

College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea; Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea; Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea; Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea.College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea; Innovative Drug Center, Duksung Women's University, Seoul 01369, Republic of Korea. Electronic address: whchung23@duksung.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30223018

Citation

Choi, Ji Eun, et al. "Lack of Superoxide Dismutase in a Rad51 Mutant Exacerbates Genomic Instability and Oxidative Stress-mediated Cytotoxicity in Saccharomyces Cerevisiae." Free Radical Biology & Medicine, vol. 129, 2018, pp. 97-106.
Choi JE, Heo SH, Kim MJ, et al. Lack of superoxide dismutase in a rad51 mutant exacerbates genomic instability and oxidative stress-mediated cytotoxicity in Saccharomyces cerevisiae. Free Radic Biol Med. 2018;129:97-106.
Choi, J. E., Heo, S. H., Kim, M. J., & Chung, W. H. (2018). Lack of superoxide dismutase in a rad51 mutant exacerbates genomic instability and oxidative stress-mediated cytotoxicity in Saccharomyces cerevisiae. Free Radical Biology & Medicine, 129, 97-106. https://doi.org/10.1016/j.freeradbiomed.2018.09.015
Choi JE, et al. Lack of Superoxide Dismutase in a Rad51 Mutant Exacerbates Genomic Instability and Oxidative Stress-mediated Cytotoxicity in Saccharomyces Cerevisiae. Free Radic Biol Med. 2018;129:97-106. PubMed PMID: 30223018.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of superoxide dismutase in a rad51 mutant exacerbates genomic instability and oxidative stress-mediated cytotoxicity in Saccharomyces cerevisiae. AU - Choi,Ji Eun, AU - Heo,Seo-Hee, AU - Kim,Myung Ju, AU - Chung,Woo-Hyun, Y1 - 2018/09/14/ PY - 2018/06/21/received PY - 2018/09/06/revised PY - 2018/09/13/accepted PY - 2018/9/18/pubmed PY - 2019/10/1/medline PY - 2018/9/18/entrez KW - DNA damage checkpoint KW - Double-strand break KW - Homologous recombination KW - Rad51 KW - Reactive oxygen species KW - Sod1 SP - 97 EP - 106 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 129 N2 - 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. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/30223018/Lack_of_superoxide_dismutase_in_a_rad51_mutant_exacerbates_genomic_instability_and_oxidative_stress_mediated_cytotoxicity_in_Saccharomyces_cerevisiae_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(18)31111-0 DB - PRIME DP - Unbound Medicine ER -