DNA damage is reported to lead to activation of the Caspase-2 — and NEMO — PIDDosome, resulting in either mitochondrial cell death or pro-inflammatory NF-kB activation and cytokine expression. In response to supernumerary centrosomes, PIDDosome formation leads to p53 stabilization and p21-dependent cell cycle arrest. Under specific circumstances, e.g. after UV irradiation, PIDD1 associates with PCNA to promote Polη-mediated translesion DNA synthesis. Finally, interstrand DNA crosslinks (ICLs) that cannot be resolved in time trigger the formation of the Caspase-2 — PIDDosome via recruitment of PIDD1-CC to FANCI.