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The High-Affinity Interaction between ORC and DNA that Is Required for Replication Licensing Is Inhibited by 2-Arylquinolin-4-Amines

Lookup NU author(s): Dr Emma Haagensen

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 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.

Publication metadata

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

Year: 2017

Volume: 24

Issue: 8

Pages: 981-992.e4

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

URL: https://doi.org/10.1016/j.chembiol.2017.06.019

DOI: 10.1016/j.chembiol.2017.06.019

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