Isorhamnetin Promotes 53BP1 Recruitment through the Enhancement of ATM Phosphorylation and Protects Mice from Radiation Gastrointestinal Syndrome

Abstract

Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we revealed that isorhamnetin inhibited radiation cell death, and investigated its action mechanism focusing on DNA damage response. Although isorhamnetin moderated p53 activity, it promoted phosphorylation of ataxia telangiectasia mutated (ATM) and enhanced 53BP1 recruitment in irradiated cells. The radioprotective effect of isorhamnetin was not observed in the presence of ATM inhibitor, indicating that its protective effect was dependent on ATM. Furthermore, isorhamnetin-treated mice survived gastrointestinal death caused by a lethal dose of abdominal irradiation. These findings suggested that isorhamnetin enhances the ATM-dependent DNA repair process, which is presumably associated with the suppressive effect against GI syndrome.

Ionizing radiation triggers mitophagy to enhance DNA damage in cancer cells

“…53BP1 (p53 binding protein 1) is an intermediary protein of considerable size that possesses the Tudor domain and necessitates its localization to sites of DNA damage. Foci are created through the swift recruitment of 53BP1 in proximity to DNA damage, which is induced by the ATM or ATR-mediated DDR signaling pathway [11]. Moreover, Chk1 promotes the phosphorylation of BRCA1, which is necessary for the proper localization of 53BP1 at the DNA damage site [2].…”

Research progress on antitumor effects of sea buckthorn, a traditional Chinese medicine homologous to food and medicine

“…Isorhamnetin is therefore thought to be a possible component in the prevention of liver disease ( 64 ). Because isorhamnetin can encourage ATM activation and the recruitment of DNA repair factor 53BP1 in irradiated cells, it can prevent the development of radioactive gastrointestinal syndrome in mice ( 65 ).…”

Radiation injury and gut microbiota-based treatment

“…Isorhamnetin, a flavonoid and a subclass of polyphenols, has been found to moderate p53 activity and promote the phosphorylation of ATM, leading to enhanced 53BP1 (the mediator protein for repairing DSB) recruitment in irradiated cells, and improve survival in mice subjected to a lethal dose of abdominal irradiation ( Shibata and Jeggo 2020 ). However, the radioprotective effect of isorhamnetin was not observed in the presence of an ATM inhibitor, indicating its protective effect is dependent on ATM ( Nishiyama et al . 2021 ).…”