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The NUCKS1-SKP2-p21/p27 axis controls S phase entry

Author

Listed:
  • Samuel Hume

    (University of Oxford)

  • Claudia P. Grou

    (University of Oxford)

  • Pauline Lascaux

    (University of Oxford)

  • Vincenzo D’Angiolella

    (University of Oxford)

  • Arnaud J. Legrand

    (University of Oxford
    The Institute of Cancer Research)

  • Kristijan Ramadan

    (University of Oxford)

  • Grigory L. Dianov

    (University of Oxford
    Siberian Branch of the Russian Academy of Sciences
    Novosibirsk State University)

Abstract

Efficient entry into S phase of the cell cycle is necessary for embryonic development and tissue homoeostasis. However, unscheduled S phase entry triggers DNA damage and promotes oncogenesis, underlining the requirement for strict control. Here, we identify the NUCKS1-SKP2-p21/p27 axis as a checkpoint pathway for the G1/S transition. In response to mitogenic stimulation, NUCKS1, a transcription factor, is recruited to chromatin to activate expression of SKP2, the F-box component of the SCFSKP2 ubiquitin ligase, leading to degradation of p21 and p27 and promoting progression into S phase. In contrast, DNA damage induces p53-dependent transcriptional repression of NUCKS1, leading to SKP2 downregulation, p21/p27 upregulation, and cell cycle arrest. We propose that the NUCKS1-SKP2-p21/p27 axis integrates mitogenic and DNA damage signalling to control S phase entry. The Cancer Genome Atlas (TCGA) data reveal that this mechanism is hijacked in many cancers, potentially allowing cancer cells to sustain uncontrolled proliferation.

Suggested Citation

  • Samuel Hume & Claudia P. Grou & Pauline Lascaux & Vincenzo D’Angiolella & Arnaud J. Legrand & Kristijan Ramadan & Grigory L. Dianov, 2021. "The NUCKS1-SKP2-p21/p27 axis controls S phase entry," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27124-8
    DOI: 10.1038/s41467-021-27124-8
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    References listed on IDEAS

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    1. Tarig Bashir & N. Valerio Dorrello & Virginia Amador & Daniele Guardavaccaro & Michele Pagano, 2004. "Control of the SCFSkp2–Cks1 ubiquitin ligase by the APC/CCdh1 ubiquitin ligase," Nature, Nature, vol. 428(6979), pages 190-193, March.
    2. Swagata Halder & Ignacio Torrecilla & Martin D. Burkhalter & Marta Popović & John Fielden & Bruno Vaz & Judith Oehler & Domenic Pilger & Davor Lessel & Katherine Wiseman & Abhay Narayan Singh & Ioland, 2019. "SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    3. Ken Tajima & Satoru Matsuda & Toshifumi Yae & Benjamin J. Drapkin & Robert Morris & Myriam Boukhali & Kira Niederhoffer & Valentine Comaills & Taronish Dubash & Linda Nieman & Hongshan Guo & Neelima K, 2019. "SETD1A protects from senescence through regulation of the mitotic gene expression program," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    4. Morgane Macheret & Thanos D. Halazonetis, 2018. "Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress," Nature, Nature, vol. 555(7694), pages 112-116, March.
    5. Simon R. Bushell & Ashley C. W. Pike & Maria E. Falzone & Nils J. G. Rorsman & Chau M. Ta & Robin A. Corey & Thomas D. Newport & John C. Christianson & Lara F. Scofano & Chitra A. Shintre & Annamaria , 2019. "The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
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