THE ROLE OF ATAXIA TELANGIECTASIA MUTATED AND THE CATALYTIC SUBUNIT OF DNA-DEPENDENT PROTEIN KINASE DURING ADIPOGENESIS

Abstract

Ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), are DNA damage response (DDR) proteins that have well established roles in the repair of DNA double strand breaks (DSBs). A growing body of scientific evidence suggests that these kinases have important, but not yet well-understood, immune and metabolic functions. ATM and DNA-PKcs can regulate cellular oxidative stress and combat reactive oxygen species (ROS) (Chen et al 2012). Since oxidative stress is a driving factor in the pathogenesis of many obesity related complications, ATM and DNA-PKcs may help respond to and regulate oxidative stress in adipocytes. Precise oxidative signaling is necessary for adipocyte differentiation and lipid accumulation. Selenium, a nutrient with suspected insulin mimetic properties, can alter cellular oxidative stress (H Gandhi et al 2013). Therefore, it is plausible that selenium may affect adipogenesis and change lipid accumulation patterns in cells. The primary research questions were as follows: What is the role of ATM and DNA-PKcs in adipogenesis and adipocyte homeostasis? Are the actions of these kinases in adipocytes explained by changes in oxidative stress levels? Do proposed nutrients with insulin mimetic properties, like selenium, affect adipogenesis via the suspected ATM - DNA-PKcs - ROS pathway? Time dependent mammalian cell culture based experiments that measured outcome variables like lipid accumulation, senescence activity, protein expression and ROS levels were conducted to assess the action of ATM and DNA-PKcs during adipogenesis and the effect of selenium on the ATM - DNA-PKcs - ROS dependent adipogenic pathway. This study found that ATM and DNA-PKcs are necessary proteins for maintaining adipocyte integrity as well as having a significant role in the differentiation of preadipocyte to adipocyte. Furthermore, we confirmed that the kinases act via a ROS dependent pathway and that dietary nutrients, such as selenium, can exert additional control over this pathway, therefore highlighting the impact adipocyte metabolism exerts over total metabolic health.