RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer.
Cell Chem Biol
; 27(1): 105-121.e14, 2020 01 16.
Article
in En
| MEDLINE
| ID: mdl-31883965
ABSTRACT
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Carrier Proteins
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Carcinoma, Non-Small-Cell Lung
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DNA Helicases
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Multiprotein Complexes
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DNA Replication
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ATPases Associated with Diverse Cellular Activities
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Lung Neoplasms
Type of study:
Diagnostic_studies
Limits:
Humans
Language:
En
Year:
2020
Type:
Article