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Genomic stability is constantly threatened by DNA damage, caused by numerous environmental and intrinsic sources, including radiation, chemicals and oncogene expression. Consequently, cells have evolved a sophisticated signal transduction network to sense DNA damage and to mount an appropriate DNA damage response. Dysregulation of the DNA damage response leads to genomic instability and cancer. Dependent on the cellular background and extent of DNA damage, the DNA damage response triggers cell cycle arrest and DNA repair, or in the case of irreparable damage, inactivation of the cells by senescence or apoptosis. In this minireview, we concentrate on the apoptotic response to DNA damage and signalling pathways linked to the cell nucleus and nuclear bodies, with a particular focus on the molecular players p53 and p73 and on the DNA damage-activated kinase homeodomain-interacting protein kinase 2 (HIPK2).