The High-Affinity Interaction between ORC and DNA that Is Required for Replication Licensing Is Inhibited by 2-Arylquinolin-4-Amines. Issue 8 (17th August 2017)

• Record Type: Journal Article
• Authors: Gardner, Nicola J.; Gillespie, Peter J.; Carrington, Jamie T.; Shanks, Emma J.; McElroy, Stuart P.; Haagensen, Emma J.; Frearson, Julie A.; Woodland, Andrew; Blow, J. Julian
• Is Part Of: Cell chemical biology. Volume 24:Issue 8(2017)
• Page Start: 981
• Page End: 992.e4
• Publication Date: 2017-08-17
• Subjects: replication licensing -- MCM2–7 -- ORC -- cancer therapeutics; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.06.019
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: In late mitosis and G1, origins of DNA replication must be "licensed" for use in the upcoming S phase by being encircled by double hexamers of the minichromosome maintenance proteins MCM2–7. A "licensing checkpoint" delays cells in G1 until sufficient origins have been licensed, but this checkpoint is lost in cancer cells. Inhibition of licensing can therefore kill cancer cells while only delaying normal cells in G1 . In a high-throughput cell-based screen for licensing inhibitors we identified a family of 2-arylquinolin-4-amines, the most potent of which we call RL5a. The binding of the origin recognition complex (ORC) to origin DNA is the first step of the licensing reaction. We show that RL5a prevents ORC forming a tight complex with DNA that is required for MCM2–7 loading. Formation of this ORC-DNA complex requires ATP, and we show that RL5a inhibits ORC allosterically to mimic a lack of ATP. Graphical Abstract: Highlights: Arylquinolin-amines identified as small-molecule inhibitors of replication licensing Inhibitor prevents tight ORC-DNA interaction required for MCM2–7 loading ORC-DNA binding inhibited allosterically to mimic a lack of ATP Abstract : Gardner et al. describe the identification of a family of arylquinolin-amines as inhibitors of "replication licensing", the loading of replication origins with double hexamers of MCM2–7. Arylquinolin-amines prevent the tight ORC-DNA interaction required for licensing, mimicking a lack of ATP.