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TSG101 associates with PARP1 and is essential for PARylation and DNA damage-induced NF-κB activation. | LitMetric

AI Article Synopsis

  • Researchers discovered that the tumor susceptibility gene TSG101 plays a crucial role in the DNA damage response by facilitating the activation of PARP1 and the formation of a specific signalosome that initiates IKK and NF-κB pathways.
  • TSG101 is necessary for effective DNA repair and cellular protection against apoptosis, and its absence leads to faulty interactions with PARP1 during DNA damage response, comparable to the effects of PARP inhibition.
  • In breast cancer cells, loss of TSG101, especially when paired with non-functional BRCA1/2 tumor suppressors, results in lethality, suggesting that targeting TSG101 could be an effective strategy for cancer therapy.

Article 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 the 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9627669PMC
http://dx.doi.org/10.15252/embj.2021110372DOI Listing

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