The Ubiquitin Ligase TRIP12 Limits PARP1 Trapping and Constrains PARP Inhibitor Efficiency.
Amino Acid Sequence
Carrier Proteins
/ chemistry
Cell Line, Tumor
DNA Damage
Down-Regulation
/ drug effects
HEK293 Cells
Humans
Models, Biological
Mutagens
/ toxicity
Neoplasms
/ pathology
Poly (ADP-Ribose) Polymerase-1
/ metabolism
Poly ADP Ribosylation
/ drug effects
Poly Adenosine Diphosphate Ribose
/ metabolism
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Proteasome Endopeptidase Complex
/ metabolism
Protein Binding
/ drug effects
Protein Domains
Protein Stability
/ drug effects
Proteolysis
/ drug effects
Signal Transduction
/ drug effects
Ubiquitin-Protein Ligases
/ chemistry
Ubiquitination
/ drug effects
BRCA mutations
HECT-type ubiquitin ligases
PAR-targeted protein ubiquitylation
PARP inhibitors
cancer
endogenous DNA lesions
genome instability
personalized cancer therapy
replication stress
synthetic lethality
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
04 08 2020
04 08 2020
Historique:
received:
17
10
2019
revised:
22
06
2020
accepted:
10
07
2020
entrez:
7
8
2020
pubmed:
7
8
2020
medline:
4
5
2021
Statut:
ppublish
Résumé
PARP inhibitors (PARPi) cause synthetic lethality in BRCA-deficient tumors. Whether specific vulnerabilities to PARPi exist beyond BRCA mutations and related defects in homology-directed repair (HDR) is not well understood. Here, we identify the ubiquitin E3 ligase TRIP12 as negative regulator of PARPi sensitivity. We show that TRIP12 controls steady-state PARP1 levels and limits PARPi-induced cytotoxic PARP1 trapping. Upon loss of TRIP12, elevated PARPi-induced PARP1 trapping causes increased DNA replication stress, DNA damage, cell cycle arrest, and cell death. Mechanistically, we demonstrate that TRIP12 binds PARP1 via a central PAR-binding WWE domain and, using its carboxy-terminal HECT domain, catalyzes polyubiquitylation of PARP1, triggering proteasomal degradation and preventing supra-physiological PARP1 accumulation. Further, in cohorts of breast and ovarian cancer patients, PARP1 abundance is negatively correlated with TRIP12 expression. We thus propose TRIP12 as regulator of PARP1 stability and PARPi-induced PARP trapping, with potential implications for PARPi sensitivity and resistance.
Identifiants
pubmed: 32755579
pii: S2211-1247(20)30970-0
doi: 10.1016/j.celrep.2020.107985
pmc: PMC7408484
pii:
doi:
Substances chimiques
Carrier Proteins
0
Mutagens
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Poly Adenosine Diphosphate Ribose
26656-46-2
TRIP12 protein, human
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
PARP1 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107985Subventions
Organisme : European Research Council
ID : 714326
Pays : International
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests M.G. and M.A. are listed as inventors on a UZH patent application for determining PARPi responsiveness.
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