Activation of DNA damage response signaling in mammalian cells by ionizing radiation
Somnath Ghosh, Asim K. Ghosh
Abstract
Cellular responses to DNA damage are fundamental to preserve genomic integrity during various endogenous and exogenous stresses. Following radiation therapy and chemotherapy, this DNA damage response (DDR) also determines development of carcinogenesis and therapeutic outcome. In humans, DNA damage activates a robust network of signal transduction cascades, driven primarily through phosphorylation events. These responses primarily involve two key non-redundant signal transducing proteins of phosphatidylinositol 3-kinase-like (PIKK) family - ATR and ATM, and their downstream kinases (hChk1 and hChk2). They further phosphorylate effectors proteins such as p53, Cdc25A and Cdc25C which function either to activate the DNA damage checkpoints and cell death mechanisms, or DNA repair pathways. Identification of molecular pathways that determine signaling after DNA damage and trigger DNA repair in response to differing types of DNA lesions allows for a far better understanding of the consequences of radiation and chemotherapy on normal and tumor cells. Here we highlight the network of DNA damage response pathways that are activated after treatment with different types of radiation. Further, we discuss regulation of cell cycle checkpoint and DNA repair processes in the context of DDR in response to radiation.