Figure 8.

PIDD mediates NF-κB activation in response to DNA damage. Upon DNA damage, genotoxic stress is detected by PIDD, which causes its nuclear translocation and/or retention, allowing PIDD to accumulate in the nucleus and interact with RIP1 and NEMO, both of which are already present in the nucleus. NEMO sumoylation and RIP1 modification then ensue. In parallel, genotoxic stress can also activate protein kinase ATM, which phosphorylates sumoylated NEMO, leading to ubiquitination, nuclear export of NEMO, and subsequent IKK activation in the cytoplasm. ATM then cause cell-cycle arrest by activation of the p53 pathway and eventually repair of the damaged DNA. However, excessive DNA damage activates an apoptotic program to avoid possible cellular transformation. In addition to PIDD, DNA-damage-induced p53 transcriptional activity also leads to the induction of proapoptotic genes such as Bax, Puma, or Noxa. Transcription of PIDD and consequent activation of caspase-2, together with the activation of the other p53-dependent proapoptotic genes, eventually lead apoptosis. p53 can also indirectly activate PIDD and PIDD, thus acts as a molecular switch between survival or apoptosis, with the final outcome probably governed by the levels of damage.