Peroxiredoxin 1 (Prx1) is a key antioxidant enzyme that maintains redox homeostasis by eliminating reactive oxygen species (ROS). Prx1-deficient mice exhibit reduced lifespan, hemolytic anemia, and age-dependent tumor formation, suggesting a role of ROS in tumorigenesis. To investigate the impact of chronic oxidative stress on somatic mutations, we performed whole-exome sequencing of liver and spleen tissues from 15-month-old Prx1 knockout mice. Primary cells from these mice showed elevated nuclear ROS levels and increased DNA damage, indicating ROS-driven genomic instability. Gene ontology analysis revealed enrichment in aging-associated pathways, including DNA damage response and cognitive processes, as well as oxidoreductase activity and DNA binding functions. Mutational signature analysis showed an age-related increase in SBS40, a signature linked to aging and human cancers. Comparative analysis of shared mutation profiles identified 16 candidate genes. Among them, Nek4 harbored an age-dependent stop-gain mutation, suggesting its potential role in ROS-associated tumorigenesis. These results characterize the mutational landscape under chronic oxidative stress and provide insight into the link between ROS accumulation, aging-related mutations, and cancer development.

Co-authors: Jiheon Shin, Sang Won Kang, Sanghyuk Lee