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

Nicola J. Gardner, Peter J. Gillespie, Jamie T. Carrington, Emma J. Shanks, Stuart P. McElroy, Emma J. Haagensen, Julie A. Frearson, Andrew Woodland (Lead / Corresponding author), J. Julian Blow (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)981-992.e4
Number of pages16
JournalCell Chemical Biology
Volume24
Issue number8
Early online date3 Aug 2017
DOIs
Publication statusPublished - 17 Aug 2017

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Keywords

  • Journal article
  • Replication licensing
  • MCM2–7
  • ORC
  • Cancer therapeutics

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