DNA damage and the balance between survival and death in cancer biology

Key Points The constant deleterious modification of DNA by reactive molecules, endogenously or exogenously generated, is offset by protective processes that are initiated by the DNA damage response. The interplay of the diverse signalling cascades (DNA damage response) that originate from the interference of DNA lesions with replication and the transcriptome leads to the activation of DNA repair, autophagy, senescence, apoptosis and necroptosis. Aspects of how post-translational modifications of the tumour suppressor p53 determine the switch between these end points are discussed. The crosstalk between autophagy, senescence, apoptosis and regulated necrosis is also discussed, focusing on the importance of thresholds for deciding cell fate. Throughout this Review, emphasis is placed on how DNA damage and DNA repair fit within the complex cellular context. Understanding how DNA damage determines cell fate — DNA repair and cell survival or death — is important for gaining insight into carcinogenesis and in promoting successful cancer therapy. This Review describes key decision-making nodes in the complex interplay between DNA damage responses and cell fate signalling. DNA is vulnerable to damage resulting from endogenous metabolites, environmental and dietary carcinogens, some anti-inflammatory drugs, and genotoxic cancer therapeutics. Cells respond to DNA damage by activating complex signalling networks that decide cell fate, promoting not only DNA repair and survival but also cell death. The decision between cell survival and death following DNA damage rests on factors that are involved in DNA damage recognition, and DNA repair and damage tolerance, as well as on factors involved in the activation of apoptosis, necrosis, autophagy and senescence. The pathways that dictate cell fate are entwined and have key roles in cancer initiation and progression. Furthermore, they determine the outcome of cancer therapy with genotoxic drugs. Understanding the molecular basis of these pathways is important not only for gaining insight into carcinogenesis, but also in promoting successful cancer therapy. In this Review, we describe key decision-making nodes in the complex interplay between cell survival and death following DNA damage.