The high-affinity interaction between ORC and DNA that is required for replication licensing is inhibited by 2-arylquinolin-4-amines

Gardner, Nicola J., Gillespie, Peter J., Carrington, Jamie T., Shanks, Emma J., McElroy, Stuart P., Haagensen, Emma J., Frearson, Julie A., Woodland, Andrew and Blow, J. Julian (2017) The high-affinity interaction between ORC and DNA that is required for replication licensing is inhibited by 2-arylquinolin-4-amines. Cell Chemical Biology, 24 (8). 981-992.e4. ISSN 2451-9456

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Abstract

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.

Item Type:	Article
Additional Information:	Funding information: This work was supported by CR-UK program grant C303/A14301, Wellcome Trust Investigator award WT096598MA, SULSA project “Inhibitors of replication licensing as novel therapies for cancer,” and MRC-DPFS devolved portfolio award MC-G0900864.
Uncontrolled Keywords:	journal article,replication licensing,mcm2–7,orc,cancer therapeutics,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:
Depositing User:	LivePure Connector
Date Deposited:	10 Jun 2024 09:30
Last Modified:	17 Jun 2024 00:18
URI:	https://ueaeprints.uea.ac.uk/id/eprint/95423
DOI:	10.1016/j.chembiol.2017.06.019

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