Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
Nature. 2024 Sep;633(8031):932-940. doi: 10.1038/s41586-024-07888-x. Epub 2024 Sep 4.
CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression. 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 p39. 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.
CDK1 一直被认为是与 cyclin B1 结合以驱动有丝分裂进程的唯一 cyclin 依赖性激酶 (CDK) 伴侣。在这里，我们证明 CDK5 在有丝分裂期间是活跃的，并且对于维持有丝分裂保真度是必要的。CDK5 是一种非典型的 CDK，因为它在有丝分裂后神经元中的高表达和由非 cyclin 蛋白 p35 和 p39 激活。在这里，我们使用独立的化学遗传学方法，在有丝分裂期间特异性地消除 CDK5 的活性，观察到有丝分裂缺陷、核异型性和有丝分裂磷酸化组的显著改变。值得注意的是，cyclin B1 是 CDK5 的有丝分裂共因子。计算建模、与 CDK-cyclin 复合物的实验结构的比较以及突变分析的验证表明，CDK5-cyclin B1 可以形成功能性复合物。CDK5-cyclin B1 复合物的破坏可模拟有丝分裂中 CDK5 的消除。总之，我们的结果表明 cyclin B1 与 CDK5 和 CDK1 结合，并且 CDK5-cyclin B1 作为一个规范的 CDK-cyclin 复合物起作用，以确保有丝分裂保真度。
