Dynamics of estrogen-induced ROS and DNA strand break generation in estrogen receptor a-positive breast cancer

DNA repair machinery is involved in estrogen-dependent transactivation. Mounting evidence suggests that mechanisms underlying estrogen-induced DNA damage are complicated. To date estrogen-induced DNA oxidation and its impact on ERa-mediated transaction remains ambiguous. Herein, we found that the process of 17 beta-estradiol (E2)-induced ROS production can be approximately divided into two phases according to responding time and generation mechanisms. The intracellular Ca2+ fluctuation and ER alpha-dependent transcription lead to temporospatially different oxidative DNA damage. Further, we demonstrate that DNA oxidation is dispensable for estrogen-responsive gene expression. Dynamics of estrogen-induced DNA strand break generation also show two-phase pattern and topoisomerase-mediated DNA stand breaks are essential in estrogen signaling. Collectively, our findings have provided new insights into oxidative DNA damage in estrogen signaling. (C) 2022 Elsevier Inc. All rights reserved.