Figure 7. Schematic summary.

Activation of the NF‐κB pathway by DNA damage depends on PARylation‐dependent formation of a transient nuclear PARP1 signalosome complex with ATM, PIASy, and IKKγ. TSG101 is required for enzymatic PARP1 activity and PAR‐dependent DNA damage‐induced NF‐κB activation. TSG101 interacts with PARP1 and is required for the dissociation of activated PARP1 from DNA lesions. TSG101‐dependent PARylation and formation of the TSG101‐PARP1 complex are independent of the role of TSG101 in the ESCRT complex. Activation of NF‐κB through the TSG101‐PARylation axis protects cells from DNA damage‐induced apoptosis. TSG101 is also crucial for DNA repair functions and is synthetically lethal in conjunction with BRCA1/2 mutations.