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TSG101 associates with PARP1 and is essential for PARylation and DNA damage‐induced NF‐κB activation
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 P...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9627669/ https://www.ncbi.nlm.nih.gov/pubmed/36124865 http://dx.doi.org/10.15252/embj.2021110372 |
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author | Tufan, Ahmet Buğra Lazarow, Katina Kolesnichenko, Marina Sporbert, Anje von Kries, Jens Peter Scheidereit, Claus |
author_facet | Tufan, Ahmet Buğra Lazarow, Katina Kolesnichenko, Marina Sporbert, Anje von Kries, Jens Peter Scheidereit, Claus |
author_sort | Tufan, Ahmet Buğra |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9627669 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96276692022-11-14 TSG101 associates with PARP1 and is essential for PARylation and DNA damage‐induced NF‐κB activation Tufan, Ahmet Buğra Lazarow, Katina Kolesnichenko, Marina Sporbert, Anje von Kries, Jens Peter Scheidereit, Claus EMBO J Articles 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. John Wiley and Sons Inc. 2022-09-20 /pmc/articles/PMC9627669/ /pubmed/36124865 http://dx.doi.org/10.15252/embj.2021110372 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Tufan, Ahmet Buğra Lazarow, Katina Kolesnichenko, Marina Sporbert, Anje von Kries, Jens Peter Scheidereit, Claus TSG101 associates with PARP1 and is essential for PARylation and DNA damage‐induced NF‐κB activation |
title |
TSG101 associates with PARP1 and is essential for PARylation and DNA damage‐induced NF‐κB activation |
title_full |
TSG101 associates with PARP1 and is essential for PARylation and DNA damage‐induced NF‐κB activation |
title_fullStr |
TSG101 associates with PARP1 and is essential for PARylation and DNA damage‐induced NF‐κB activation |
title_full_unstemmed |
TSG101 associates with PARP1 and is essential for PARylation and DNA damage‐induced NF‐κB activation |
title_short |
TSG101 associates with PARP1 and is essential for PARylation and DNA damage‐induced NF‐κB activation |
title_sort | tsg101 associates with parp1 and is essential for parylation and dna damage‐induced nf‐κb activation |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9627669/ https://www.ncbi.nlm.nih.gov/pubmed/36124865 http://dx.doi.org/10.15252/embj.2021110372 |
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