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Cell Chem Biol 2017 Aug 17;248:981-992.e4. doi: 10.1016/j.chembiol.2017.06.019.
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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.

Gardner NJ , Gillespie PJ , Carrington JT , Shanks EJ , McElroy SP , Haagensen EJ , Frearson JA , Woodland A , Blow JJ .

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.

PubMed ID: 28781123
PMC ID: PMC5563080
Article link: Cell Chem Biol
Grant support: [+]

Species referenced: Xenopus
Genes referenced: cdc6 cdt1 gmnn lmnb1 mcm2 mcm3 mcm4 mcm5 mcm7 orc1 orc2 orc3 tuba4b
Antibodies: Lmnb1 Ab5 Tuba4b Ab3

Disease Ontology terms: cancer

Article Images: [+] show captions
References [+] :
Arias, Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. 2007, Pubmed