CDK5-cyclin B1 regulates mitotic fidelity

• 成果类型: Article
• 署名作者: Zheng, Xiao-Feng; Sarkar, Aniruddha; Lotana, Humphrey; Syed, Aleem; Nguyen, Huy; Ivey, Richard G.; Kennedy, Jacob J.; Whiteaker, Jeffrey R.; Tomasik, Bartlomiej; Huang, Kaimeng; Li, Feng; DAndrea, Alan D.; Paulovich, Amanda G.; Shah, Kavita; Spektor, Alexander; Chowdhury, Dipanjan
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Purdue University System; Purdue University; Purdue University System; Purdue University; Fred Hutchinson Cancer Center; Medical University Lodz; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Fahrenheit Universities; Medical University Gdansk
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6447
• DOI: 10.1038/s41586-024-07888-x
• 发表日期: 2024-09-26
• 关键词: microtubule attachment; computational platform; distinct roles; cell-cycle; protein; phosphorylation; complex; cdk1; activation; expression

摘要

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. Cyclin B1 is a mitotic co-factor of CDK5.