| Literature DB >> 31883965 |
Paul Yenerall1, Amit K Das2, Shan Wang3, Rahul K Kollipara4, Long Shan Li2, Pamela Villalobos5, Josiah Flaming2, Yu-Fen Lin6, Kenneth Huffman2, Brenda C Timmons2, Collin Gilbreath7, Rajni Sonavane7, Lisa N Kinch8, Jaime Rodriguez-Canales5, Cesar Moran9, Carmen Behrens10, Makoto Hirasawa11, Takehiko Takata12, Ryo Murakami13, Koichi Iwanaga12, Benjamin P C Chen6, Nick V Grishin8, Ganesh V Raj14, Ignacio I Wistuba15, John D Minna16, Ralf Kittler17.
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.Entities:
Keywords: DNA replication; RUVBL1; RUVBL2; non-small cell lung cancer; radiation therapy
Mesh：
Substances：
Year: 2019 PMID： 31883965 PMCID： PMC8048778 DOI： 10.1016/j.chembiol.2019.12.005
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 8.116