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TSG101 Associates with PARP1 and is Essential for PARylation and DNA Damage-induced NF-κB Activation

ABSTRACT: In a genome-wide screening for components of the dsDNA-break-induced IKK-NF-κB pathway we identified scores of regulators, including Tumor Susceptibility Gene TSG101. TSG101 is essential for DNA damage-induced formation of cellular poly(ADP-ribose) (PAR). TSG101 binds to PARP1 and is required for PARP1 activation. This function of TSG101 is independent of its role in the ESCRT-I endosomal sorting complex. In the absence of TSG101, the PAR-dependent formation of a nuclear PARP1-IKKγ signalosome, which triggers IKK activation, is impaired. According to its requirement for PARP1 and NF-κB activation, TSG101 deficient cells are defective in DNA repair and apoptosis protection. Loss of TSG101 results in PARP1 trapping at damage sites and mimics the effect of pharmacological PARP-inhibition. We also show that loss of TSG101 in connection with inactivated tumor suppressors BRCA1/2 in breast cancer cells is lethal. Our results imply TSG101 as a therapeutic target to achieve synthetic lethality in cancer treatment.

SUBMITTER: Dr. Ahmet, Buğra Tufan

PROVIDER: S-SCDT-EMBOJ-2021-110372 | biostudies-other |

REPOSITORIES: biostudies-other

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