RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer.
ATPases Associated with Diverse Cellular Activities
/ antagonists & inhibitors
Antineoplastic Agents
/ chemistry
Carcinoma, Non-Small-Cell Lung
/ diagnosis
Carrier Proteins
/ antagonists & inhibitors
DNA Helicases
/ antagonists & inhibitors
DNA Replication
/ drug effects
Enzyme Inhibitors
/ chemistry
Humans
Lung Neoplasms
/ diagnosis
Molecular Structure
Multiprotein Complexes
/ antagonists & inhibitors
Radiation Tolerance
DNA replication
RUVBL1
RUVBL2
non-small cell lung cancer
radiation therapy
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
16 01 2020
16 01 2020
Historique:
received:
28
06
2019
revised:
07
11
2019
accepted:
06
12
2019
pubmed:
31
12
2019
medline:
16
3
2021
entrez:
30
12
2019
Statut:
ppublish
Résumé
RUVBL1 and RUVBL2 (collectively RUVBL1/2) are essential AAA+ ATPases that function as co-chaperones and have been implicated in cancer. Here we investigated the molecular and phenotypic role of RUVBL1/2 ATPase activity in non-small cell lung cancer (NSCLC). We find that RUVBL1/2 are overexpressed in NSCLC patient tumors, with high expression associated with poor survival. Utilizing a specific inhibitor of RUVBL1/2 ATPase activity, we show that RUVBL1/2 ATPase activity is necessary for the maturation or dissociation of the PAQosome, a large RUVBL1/2-dependent multiprotein complex. We also show that RUVBL1/2 have roles in DNA replication, as inhibition of its ATPase activity can cause S-phase arrest, which culminates in cancer cell death via replication catastrophe. While in vivo pharmacological inhibition of RUVBL1/2 results in modest antitumor activity, it synergizes with radiation in NSCLC, but not normal cells, an attractive property for future preclinical development.
Identifiants
pubmed: 31883965
pii: S2451-9456(19)30401-5
doi: 10.1016/j.chembiol.2019.12.005
pmc: PMC8048778
mid: NIHMS1682340
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Carrier Proteins
0
Enzyme Inhibitors
0
Multiprotein Complexes
0
ATPases Associated with Diverse Cellular Activities
EC 3.6.4.-
DNA Helicases
EC 3.6.4.-
RUVBL1 protein, human
EC 3.6.4.12
RUVBL2 protein, human
EC 3.6.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
105-121.e14Subventions
Organisme : NCI NIH HHS
ID : R01 CA124633
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM127390
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA223828
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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