DSB-induced oxidative stress: Uncovering crosstalk between DNA damage response and cellular metabolism

• Published in: DNA repair Vol. 141; p. 103730
• Main Authors: Li, Xinyu, Yang, Caini, Wu, Hengyu, Chen, Hongran, Gao, Xing, Zhou, Sa, Zhang, Tong-Cun, Ma, Wenjian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2024
• Subjects: Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Checkpoint Kinase 2 - genetics; Checkpoint Kinase 2 - metabolism; DNA Breaks, Double-Stranded; DNA Damage; DNA End-Joining Repair; DNA Repair; DSB; Homologous Recombination; Oxidative Stress; Reactive Oxygen Species - metabolism; Recombinational DNA Repair; ROS; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; DSB; ROS; DNA Damage
• ISSN: 1568-7864; 1568-7856; 1568-7856
• DOI: 10.1016/j.dnarep.2024.103730

While that ROS causes DNA damage is well documented, there has been limited investigation into whether DNA damages and their repair processes can conversely induce oxidative stress. By generating a site-specific DNA double strand break (DSB) via I-SceI endonuclease expression in S. cerevisiae without damaging other cellular components, this study demonstrated that DNA repair does trigger oxidative stress. Deleting genes participating in the initiation of the resection step of homologous recombination (HR), like the MRX complex, resulted in stimulation of ROS. In contrast, deleting genes acting downstream of HR resection suppressed ROS levels. Additionally, blocking non-homologous end joining (NHEJ) also suppressed ROS. Further analysis identified Rad53 as a key player that relays DNA damage signals to alter redox metabolism in an HR-specific manner. These results suggest both HR and NHEJ can drive metabolism changes and oxidative stress, with NHEJ playing a more prominent role in ROS stimulation. Further analysis revealed a correlation between DSB-induced ROS increase and enhanced activity of NADPH oxidase Yno1 and various antioxidant enzymes. Deleting the antioxidant gene SOD1 induced synthetic lethality in HR-deficient mutants like mre11Δ and rad51Δ upon DSB induction. These findings uncover a significant interplay between DNA repair mechanisms and cellular metabolism, providing insights into understanding the side effects of genotoxic therapies and potentially aiding development of more effective cancer treatment strategies. •DNA double-strand break (DSB) repair signaling elicits oxidative stress.•HR and NHEJ both stimulate reactive oxygen species with NHEJ playing a more prominent role.•Rad53 relays DNA damage signals to alter redox metabolism in an HR-specific manner.•Enhanced activity of NADPH oxidase and antioxidant enzymes follows generation of a single DSB.•SOD1 deletion induces synthetic lethality in some HR-deficient mutants.