Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical genetics

Anastasia Sosenko Piscitello, Ann-Sofie Nilsson, Michael Hawgood, Abid H. Sayyid, Vasilis S. Dionellis, Giovanni Giglio, Bruno Urién, Pratikiran Bajgain, Sotirios G. Ntallis, Jiri Bartek (), Thanos D. Halazonetis () and Bennie Lemmens ()
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Anastasia Sosenko Piscitello: University of Geneva
Ann-Sofie Nilsson: Science for Life Laboratory
Michael Hawgood: Science for Life Laboratory
Abid H. Sayyid: Science for Life Laboratory
Vasilis S. Dionellis: University of Geneva
Giovanni Giglio: Science for Life Laboratory
Bruno Urién: Science for Life Laboratory
Pratikiran Bajgain: Science for Life Laboratory
Sotirios G. Ntallis: University of Geneva
Jiri Bartek: Science for Life Laboratory
Thanos D. Halazonetis: University of Geneva
Bennie Lemmens: Science for Life Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Cyclin-dependent kinases (CDKs) coordinate DNA replication and cell division, and play key roles in tissue homeostasis, genome stability and cancer development. The first step in replication is origin licensing, when minichromosome maintenance (MCM) helicases are loaded onto DNA by CDC6, CDT1 and the origin recognition complex (ORC). In yeast, origin licensing starts when CDK activity plummets in G1 phase, reinforcing the view that CDKs inhibit licensing. Here we show that, in human cells, CDK4/6 activity promotes origin licensing. By combining rapid protein degradation and time-resolved EdU-sequencing, we find that CDK4/6 activity acts epistatically to CDC6 and CDT1 in G1 phase and counteracts RB pocket proteins to promote origin licensing. Therapeutic CDK4/6 inhibitors block MCM and ORC6 loading, which we exploit to trigger mitosis with unreplicated DNA in p53-deficient cells. The CDK4/6-RB axis thus links replication licensing to proliferation, which has implications for human cell fate control and cancer therapy design.

Date: 2025
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DOI: 10.1038/s41467-025-63669-8

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