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

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Item Type:

Article

Title:

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

Creators Name:

Tufan, A.B. and Lazarow, K. and Kolesnichenko, M. and Sporbert, A. and von Kries, J.P. and Scheidereit, C.

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.

Keywords:

ADP Ribosylation, Breast Cancer, DNA Damage, IKK-NF-jB Pathway, TSG101

Source:

EMBO Journal

ISSN:

0261-4189

Publisher:

EMBO Press / Wiley

Volume:

Number:

Page Range:

e110372

Date:

2 November 2022

Official Publication:

https://doi.org/10.15252/embj.2021110372

PubMed:

View item in PubMed

Related to:

URL	URL Type
https://edoc.mdc-berlin.de/21158/	Preprint version

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