2. Academic Validation
  3. CDK5-cyclin B1 regulates mitotic fidelity

CDK5-cyclin B1 regulates mitotic fidelity

  • Nature. 2024 Sep;633(8031):932-940. doi: 10.1038/s41586-024-07888-x.
Xiao-Feng Zheng # 1,  Aniruddha Sarkar # 1,  Humphrey Lotana 2,  Aleem Syed 1,  Huy Nguyen 1,  Richard G Ivey 3,  Jacob J Kennedy 3,  Jeffrey R Whiteaker 3,  Bartłomiej Tomasik 1 4 5,  Kaimeng Huang 1 6,  Feng Li 1,  Alan D D'Andrea 1 6,  Amanda G Paulovich 3,  Kavita Shah 2,  Alexander Spektor 7 8,  Dipanjan Chowdhury 9 10 11
Affiliations

Affiliations

  • 1 Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
  • 3 Translational Science and Therapeutics Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 4 Department of Biostatistics and Translational Medicine, Medical University of Łódź, Łódź, Poland.
  • 5 Department of Oncology and Radiotherapy, Medical University of Gdańsk, Faculty of Medicine, Gdańsk, Poland.
  • 6 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 7 Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Alexander_Spektor@dfci.harvard.edu.
  • 8 Broad Institute of Harvard and MIT, Cambridge, MA, USA. Alexander_Spektor@dfci.harvard.edu.
  • 9 Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Dipanjan_Chowdhury@dfci.harvard.edu.
  • 10 Broad Institute of Harvard and MIT, Cambridge, MA, USA. Dipanjan_Chowdhury@dfci.harvard.edu.
  • 11 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Dipanjan_Chowdhury@dfci.harvard.edu.
  • # Contributed equally.
PMID: 39232161 DOI: 10.1038/s41586-024-07888-x
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.

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