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

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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
    Luleå University of Technology)

  • 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
    Danish Cancer Institute)

  • Thanos D. Halazonetis

    (University of Geneva)

  • Bennie Lemmens

    (Science for Life Laboratory)

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.

Suggested Citation

  • 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 & Th, 2025. "Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical genetics," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63669-8
    DOI: 10.1038/s41467-025-63669-8
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