PIDD Mediates NF-κB Activation in Response to DNA Damage

Activation of NF-kB following genotoxic stress allows time for DNA-damage repair and ensures cell survival accounting for acquired chemoresistance, an impediment to effective cancer therapy. Despite this clinical relevance, little is known about pathways that enable genotoxic-stress-induced NF-kB induction. Previously, we reported a role for the p53-inducible death-domaincontaining protein, PIDD, in caspase-2 activation and apoptosis in response to DNA damage. We now demonstrate that PIDD plays a critical role in DNA-damage-induced NF-kB activation. Upon genotoxic stress, a complex between PIDD, the kinase RIP1, and a component of the NF-kB-activating kinase complex, NEMO, is formed. PIDD expression enhances genotoxic-stress-induced NF-kB activation through augmented sumoylation and ubiquitination of NEMO. Depletion of PIDD and RIP1, but not caspase-2, abrogates DNA-damage-induced NEMO modification and NF-kB activation. We propose that PIDD acts as a molecular switch, controlling the balance between life and death upon DNA damage.