Ceramide Regulates MRN Complex‐ATM‐Dependent Apoptotic Pathway in Human Lymphoblastoids

Abstract

Ceramide is a key lipid second messenger for apoptotic stresses. However, it remains unknown how ceramide is involved in genotoxic apoptotic pathway such as DNA double-strand breaks (DSBs). Ataxia telangiectasia mutated (ATM) plays crucial roles in cellular responses including DNA repair, cell cycle control and apoptosis following DNA DSBs. We herein demonstrated the requirement of ceramide for ATM signaling in genotoxic drug neocarzinostatin (NCS)-induced apoptotic pathway in lymphoblastoids. NCS treatment produces ceramide by synergistic effect of neutral sphingomyelinase (SMase) activation and sphingomyelin synthase (SMS) inactivation. The ceramide production activates ATM and leads to caspase-3-dependent apoptosis. Nuclear study indicates that ceramide regulates ATM activity through MRN (Mre11/ Rad50/NBS1) complex that is a primary factor to detect DSBs (figure). Thus, we demonstrate that ceramide acts as an early trigger for the activation of MRN complex-ATM pathway in nuclear upon DNA damage stress, and finally exert caspase-3-dependent apoptosis.