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Lookup NU author(s): Dr Emma Haagensen
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 The Authors 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.
Author(s): Gardner NJ, Gillespie PJ, Carrington JT, Shanks EJ, McElroy SP, Haagensen EJ, Frearson JA, Woodland A, Blow JJ
Publication type: Article
Publication status: Published
Journal: Cell Chemical Biology
Online publication date: 03/08/2017
Acceptance date: 30/06/2017
Date deposited: 12/10/2017
ISSN (print): 2451-9456
ISSN (electronic): 2451-9448
Publisher: Elsevier Ltd
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