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

Paul Yenerall, Amit 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 IwanagaBenjamin P.C. Chen, Nick V. Grishin, Ganesh V. Raj, Ignacio I. Wistuba, John D. Minna, Ralf Kittler

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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. Yenerall et al. identified a specific inhibitor of RUVBL1/2 ATPase activity, compound B, and demonstrate that RUVBL1/2 ATPase activity is required for PAQosome maturation/dissociation. Compound B kills non-small cell lung cancer (NSCLC) by inhibiting DNA replication. In addition, compound B radiosensitizes NSCLC, but not normal cells, an attractive property for future development.

Original languageEnglish (US)
Pages (from-to)105-121.e14
JournalCell Chemical Biology
Volume27
Issue number1
DOIs
StatePublished - Jan 16 2020

Keywords

  • DNA replication
  • RUVBL1
  • RUVBL2
  • non-small cell lung cancer
  • radiation therapy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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