Cellular Stress Responses: Cell Survival and Cell Death

Figure 3

DNA damage responses and cell death. Upon exposure to ionizing radiation or genotoxins, the damage to DNA is a common initial event. DNA double strand breaks (DSBs) or single strand breaks (SSBs) are considered to be key lesions that initiate activation of the DNA damage response. Upon DSBs, ataxia telangiectasia mutated (ATM) is recruited by the MRE-11-Rad50-NBS1 (MRN) complex to sites of broken DNA and phosphorylates downstream substrates such as checkpoint kinase 2 (Chk2), which subsequently phosphorylates p53. Sublethal damage to DNA can engage survival pathways via p21-mediated cell cycle arrest. Alternatively—if the damage is too severe to be repaired—pro-apoptotic p53 target genes are activated including Bax, Puma, Noxa, and Fas, which promote apoptosis. Upon SSBs, it is ataxia telangiectasia and Rad3 related (ATR) that gets activated and phosphorylates Chk1. Chk1 in turn phosphorylates and inhibits cdc25c to mediated G2/M arrest or alternatively cdc25a to promote S-phase arrest.