Figures & data
Figure 1. The effects of the DNA damage response on cellular fate in response to DNA damage. In response to DNA damage, cells trigger a series of signaling cascades. Depending on the extent of DNA damage, cellular fate will be determined by DNA damage response. When the DNA damage is mild and repairable, cells will activate the signaling pathways of promoting cell survival, including DNA repair, cell cycle arrest, and autophagy. However, when the severe damage is beyond repair, cells will execute the cell death programs such as autophagy, apoptosis and necrosis to restrain the damaged cell from further expansion. Notably, autophagy plays a dual role in determining cell fate. In general, depending on the extent of DNA damage and the tumor type, the type of stimuli, autophagy could be a survival mechanism or induce programmed cell death.
Figure 2. The signaling pathways of autophagy induced by DNA damage. In response to DNA damage, ATM regulates autophagy through signaling of AMPK and TSC1/2. Meanwhile, ATM and ATR also activate p53 to induce the activation of autophagy. p53 plays an important role in autophagy regulation. On one hand, p53 positively activates AMPK and DRAM to inhibit mTOR which is an inhibitor of autophagy, thereby inducing autophagy activation. One the other hand, p53 activates PTEN, a repressor of PI3K/Akt, to inhibit mTOR and induces autophagy initiation.
Figure 3. The possible relationship between DNA repair and autophagy. Depending on the extent of DNA damage, cellular fate appears entirely differently by activating different signaling pathways. When DNA damage is mild and repairable, cytoprotective autophagy will be activated to promote cellular survival via enhancing the turnover of DNA repair proteins. Meanwhile, some of the DNA repair proteins are able to promote autophagy activation, thereby contributing to cell survival. However, when severe DNA damage is beyond repair, cells will activate cytotoxic autophagy to execute the cell death program by accelerating the degradation of DNA repair proteins. The decreased capacity of DNA repair will aggravate the induction of cytotoxic autophagy and finally result in cell death.
