title: Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability.
abstract: We report the functional and temporal relationship between cellular phenotypes such as oxidative stress, p38MAPK-dependent responses and genomic instability persisting in the progeny of cells exposed to sparsely ionizing low-Linear Energy Transfer (LET) radiation such as X-rays or high-charge and high-energy (HZE) particle high-LET radiation such as (56)Fe ions. We found that exposure to low and high-LET radiation increased reactive oxygen species (ROS) levels as a threshold-like response induced independently of radiation quality and dose. This response was sustained for two weeks, which is the period of time when genomic instability is evidenced by increased micronucleus formation frequency and DNA damage associated foci. Indicators for another persisting response sharing phenotypes with stress-induced senescence, including beta galactosidase induction, increased nuclear size, p38MAPK activation and IL-8 production, were induced in the absence of cell proliferation arrest during the first, but not the second week following exposure to high-LET radiation. This response was driven by a p38MAPK-dependent mechanism and was affected by radiation quality and dose. This stress response and elevation of ROS affected genomic instability by distinct pathways. Through interference with p38MAPK activity, we show that radiation-induced stress phenotypes promote genomic instability. In contrast, exposure to physiologically relevant doses of hydrogen peroxide or increasing endogenous ROS levels with a catalase inhibitor reduced the level of genomic instability. Our results implicate persistently elevated ROS following exposure to radiation as a factor contributing to genome stabilization.
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Erica
authors.initials: E
authors.lastname: Werner
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Huichen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Hematology and Medical Oncology Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Doetsch
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics / Q000528:radiation effects; D015870:Gene Expression; D042822:Genomic Instability / Q000528:radiation effects*; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects; D010641:Phenotype; D011827:Radiation; D011829:Radiation Dosage; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases