The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death

The maintenance of genome stability is essential for the cell as the integrity of genomic information guaranties reproduction of a whole organism. DNA damage occurring in response to different natural and nonnatural stimuli (errors in DNA replication, UV radiation, chemical agents, etc.) is normally detected by special cellular machinery that induces DNA repair. However, further accumulation of genetic lesions drives the activation of cell death to eliminate cells with defective genome. This particular feature is used for targeting fast-proliferating tumor cells during chemo-, radio-, and immunotherapy. Among different cell death modalities induced by DNA damage, apoptosis is the best studied. Nevertheless, nonapoptotic cell death and adaptive stress responses are also activated following genotoxic stress and play a crucial role in the outcome of anticancer therapy. Here, we provide an overview of nonapoptotic cell death pathways induced by DNA damage and discuss their interplay with cellular senescence, mitotic catastrophe, and autophagy.