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RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer.

Paul Yenerall | Amit K Das | Shan Wang | Rahul K Kollipara | Long Shan Li | Pamela Villalobos | Josiah Flaming | Yu-Fen Lin | Kenneth Huffman | Brenda C Timmons | Collin Gilbreath | Rajni Sonavane | Lisa N Kinch | Jaime Rodriguez-Canales | Cesar Moran | Carmen Behrens | Makoto Hirasawa | Takehiko Takata | Ryo Murakami | Koichi Iwanaga | Benjamin P C Chen | Nick V Grishin | Ganesh V Raj | Ignacio I Wistuba | John D Minna | Ralf Kittler
Cell chemical biology | 2020

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.

Pubmed ID: 31883965

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R01 CA124633
  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM127390
  • Agency: NCI NIH HHS, United States
    Id: P50 CA070907
  • Agency: NCI NIH HHS, United States
    Id: R01 CA223828
  • Agency: NCI NIH HHS, United States
    Id: P30 CA142543

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RPA14 antibody (antibody)

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