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CDK5–cyclin B1 regulates mitotic fidelity

Author

Listed:
  • Xiao-Feng Zheng

    (Harvard Medical School)

  • Aniruddha Sarkar

    (Harvard Medical School)

  • Humphrey Lotana

    (Purdue University)

  • Aleem Syed

    (Harvard Medical School)

  • Huy Nguyen

    (Harvard Medical School)

  • Richard G. Ivey

    (Fred Hutchinson Cancer Research Center)

  • Jacob J. Kennedy

    (Fred Hutchinson Cancer Research Center)

  • Jeffrey R. Whiteaker

    (Fred Hutchinson Cancer Research Center)

  • Bartłomiej Tomasik

    (Harvard Medical School
    Medical University of Łódź
    Faculty of Medicine)

  • Kaimeng Huang

    (Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Feng Li

    (Harvard Medical School)

  • Alan D. D’Andrea

    (Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Amanda G. Paulovich

    (Fred Hutchinson Cancer Research Center)

  • Kavita Shah

    (Purdue University)

  • Alexander Spektor

    (Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Dipanjan Chowdhury

    (Harvard Medical School
    Broad Institute of Harvard and MIT
    Harvard Medical School)

Abstract

CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression1. Here we demonstrate that CDK5 is active during mitosis and is necessary for maintaining mitotic fidelity. CDK5 is an atypical CDK owing to its high expression in post-mitotic neurons and activation by non-cyclin proteins p35 and p392. Here, using independent chemical genetic approaches, we specifically abrogated CDK5 activity during mitosis, and observed mitotic defects, nuclear atypia and substantial alterations in the mitotic phosphoproteome. Notably, cyclin B1 is a mitotic co-factor of CDK5. Computational modelling, comparison with experimentally derived structures of CDK–cyclin complexes and validation with mutational analysis indicate that CDK5–cyclin B1 can form a functional complex. Disruption of the CDK5–cyclin B1 complex phenocopies CDK5 abrogation in mitosis. Together, our results demonstrate that cyclin B1 partners with both CDK5 and CDK1, and CDK5–cyclin B1 functions as a canonical CDK–cyclin complex to ensure mitotic fidelity.

Suggested Citation

  • Xiao-Feng Zheng & Aniruddha Sarkar & Humphrey Lotana & Aleem Syed & Huy Nguyen & Richard G. Ivey & Jacob J. Kennedy & Jeffrey R. Whiteaker & Bartłomiej Tomasik & Kaimeng Huang & Feng Li & Alan D. D’An, 2024. "CDK5–cyclin B1 regulates mitotic fidelity," Nature, Nature, vol. 633(8031), pages 932-940, September.
    • Handle: RePEc:nat:nature:v:633:y:2024:i:8031:d:10.1038_s41586-024-07888-x
    DOI: 10.1038/s41586-024-07888-x
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