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Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication

Author

Listed:
  • Piers Nash

    (Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital)

  • Xiaojing Tang

    (Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital)

  • Stephen Orlicky

    (Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital)

  • Qinghua Chen

    (L.P. Markey Cancer Center, University of Kentucky)

  • Frank B. Gertler

    (Massachusetts Institute of Technology)

  • Michael D. Mendenhall

    (L.P. Markey Cancer Center, University of Kentucky)

  • Frank Sicheri

    (Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
    University of Toronto)

  • Tony Pawson

    (Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
    University of Toronto)

  • Mike Tyers

    (Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
    University of Toronto)

Abstract

SCF ubiquitin ligases target phosphorylated substrates for ubiquitin-dependent proteolysis by means of adapter subunits called F-box proteins. The F-box protein Cdc4 captures phosphorylated forms of the cyclin-dependent kinase inhibitor Sic1 for ubiquitination in late G1 phase, an event necessary for the onset of DNA replication. The WD40 repeat domain of Cdc4 binds with high affinity to a consensus phosphopeptide motif (the Cdc4 phospho-degron, CPD), yet Sic1 itself has many sub-optimal CPD motifs that act in concert to mediate Cdc4 binding. The weak CPD sites in Sic1 establish a phosphorylation threshold that delays degradation in vivo, and thereby establishes a minimal G1 phase period needed to ensure proper DNA replication. Multisite phosphorylation may be a more general mechanism to set thresholds in regulated protein–protein interactions.

Suggested Citation

  • Piers Nash & Xiaojing Tang & Stephen Orlicky & Qinghua Chen & Frank B. Gertler & Michael D. Mendenhall & Frank Sicheri & Tony Pawson & Mike Tyers, 2001. "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication," Nature, Nature, vol. 414(6863), pages 514-521, November.
    • Handle: RePEc:nat:nature:v:414:y:2001:i:6863:d:10.1038_35107009
    DOI: 10.1038/35107009
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    Cited by:

    1. Juan Manuel Valverde & Geronimo Dubra & Michael Phillips & Austin Haider & Carlos Elena-Real & Aurélie Fournet & Emile Alghoul & Dhanvantri Chahar & Nuria Andrés-Sanchez & Matteo Paloni & Pau Bernadó , 2023. "A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    2. Maximilian Mosbacher & Sung Sik Lee & Gilad Yaakov & Mariona Nadal-Ribelles & Eulàlia Nadal & Frank Drogen & Francesc Posas & Matthias Peter & Manfred Claassen, 2023. "Positive feedback induces switch between distributive and processive phosphorylation of Hog1," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Anneke Brümmer & Carlos Salazar & Vittoria Zinzalla & Lilia Alberghina & Thomas Höfer, 2010. "Mathematical Modelling of DNA Replication Reveals a Trade-off between Coherence of Origin Activation and Robustness against Rereplication," PLOS Computational Biology, Public Library of Science, vol. 6(5), pages 1-13, May.
    4. Christopher A. Waudby & Saul Alvarez-Teijeiro & E. Josue Ruiz & Simon Suppinger & Nikos Pinotsis & Paul R. Brown & Axel Behrens & John Christodoulou & Anastasia Mylona, 2022. "An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Jacob D Feala & Jorge Cortes & Phillip M Duxbury & Andrew D McCulloch & Carlo Piermarocchi & Giovanni Paternostro, 2012. "Statistical Properties and Robustness of Biological Controller-Target Networks," PLOS ONE, Public Library of Science, vol. 7(1), pages 1-11, January.

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