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

Research output: Contribution to journalArticlepeer-review

4 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

Fingerprint Dive into the research topics of 'RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer'. Together they form a unique fingerprint.

Cite this