p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation.
CB-5083
DNA damage
DNA double-strand break repair
IR
MRE11
bladder cancer
homologous recombination
ionizing radiation
p97
single-strand annealing
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
25 05 2021
25 05 2021
Historique:
received:
05
02
2020
revised:
16
03
2021
accepted:
28
04
2021
entrez:
26
5
2021
pubmed:
27
5
2021
medline:
11
2
2022
Statut:
ppublish
Résumé
The ATPase p97 is a central component of the ubiquitin-proteasome degradation system. p97 uses its ATPase activity and co-factors to extract ubiquitinated substrates from different cellular locations, including DNA lesions, thereby regulating DNA repair pathway choice. Here, we find that p97 physically and functionally interacts with the MRE11-RAD50-NBS1 (MRN) complex on chromatin and that inactivation of p97 blocks the disassembly of the MRN complex from the sites of DNA damage upon ionizing radiation (IR). The inhibition of p97 function results in excessive 5'-DNA end resection mediated by MRE11 that leads to defective DNA repair and radiosensitivity. In addition, p97 inhibition by the specific small-molecule inhibitor CB-5083 increases tumor cell killing following IR both in vitro and in vivo. Mechanistically, this is mediated via increased MRE11 nuclease accumulation. This suggests that p97 inhibitors might be exploited to improve outcomes for radiotherapy patients.
Identifiants
pubmed: 34038735
pii: S2211-1247(21)00495-2
doi: 10.1016/j.celrep.2021.109153
pmc: PMC8170441
pii:
doi:
Substances chimiques
Nuclear Proteins
0
DNA
9007-49-2
MRE11 Homologue Protein
EC 3.1.-
Adenosine Triphosphatases
EC 3.6.1.-
p97 ATPase
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109153Subventions
Organisme : Medical Research Council
ID : MC_PC_12001/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC 12001/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5255/A23755
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00001/1
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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