RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer. Issue 1 (16th January 2020)

• Record Type: Journal Article
• Authors: Yenerall, Paul; Das, Amit K.; Wang, Shan; Kollipara, Rahul K.; Li, Long Shan; Villalobos, Pamela; Flaming, Josiah; Lin, Yu-Fen; Huffman, Kenneth; Timmons, Brenda C.; Gilbreath, Collin; Sonavane, Rajni; Kinch, Lisa N.; Rodriguez-Canales, Jaime; Moran, Cesar; Behrens, Carmen; Hirasawa, Makoto; Takata, Takehiko; Murakami, Ryo; Iwanaga, Koichi; Chen, Benjamin P.C.; Grishin, Nick V.; Raj, Ganesh V.; Wistuba, Ignacio I.; Minna, John D.; Kittler, Ralf
• Is Part Of: Cell chemical biology. Volume 27:Issue 1(2020)
• Page Start: 105
• Page End: 121.e14
• Publication Date: 2020-01-16
• Subjects: RUVBL1 -- RUVBL2 -- DNA replication -- non-small cell lung cancer -- radiation therapy; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.12.005
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Validation of compound B as a specific RUVBL1/2 ATPase inhibitor RUVBL1/2 ATPase activity is required for PAQosome, not INO80-family, complexes NSCLC requires RUVBL1/2 ATPase activity for DNA replication Compound B radiosensitizes NSCLC, but not normal lung epithelial cells Abstract : 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.