Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Laboratory of Cancer Cell Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Life Sci Alliance. 2021 Jan 5;4(3). doi: 10.26508/lsa.202000980. Print 2021 Mar.
Cyclin A2 is a key regulator of the cell cycle, implicated both in DNA replication and mitotic entry. Cyclin A2 participates in feedback loops that activate mitotic kinases in G2 phase, but why active Cyclin A2-CDK2 during the S phase does not trigger mitotic kinase activation remains unclear. Here, we describe a change in localisation of Cyclin A2 from being only nuclear to both nuclear and cytoplasmic at the S/G2 border. We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1. Expression of predominately cytoplasmic Cyclin A2 or phospho-mimicking PLK1 T210D can partially rescue a G2 arrest caused by Cyclin A2 depletion. Cytoplasmic presence of Cyclin A2 is restricted by p21, in particular after DNA damage. Cyclin A2 chromatin association during DNA replication and additional mechanisms contribute to Cyclin A2 localisation change in the G2 phase. We find no evidence that such mechanisms involve G2 feedback loops and suggest that cytoplasmic appearance of Cyclin A2 at the S/G2 transition functions as a trigger for mitotic kinase activation.
细胞周期蛋白 A2 是细胞周期的关键调节因子，既参与 DNA 复制，又参与有丝分裂进入。细胞周期蛋白 A2 参与反馈环，在 G2 期激活有丝分裂激酶，但为什么在 S 期有活性的细胞周期蛋白 A2-CDK2 不会触发有丝分裂激酶的激活仍不清楚。在这里，我们描述了细胞周期蛋白 A2 的定位从仅在核内变为 S/G2 边界处的核内和细胞质内。我们发现细胞周期蛋白 A2-CDK2 可以通过磷酸化 Bora 激活有丝分裂激酶 PLK1，并且只有细胞质细胞周期蛋白 A2 与 Bora 和 PLK1 相互作用。主要表达细胞质细胞周期蛋白 A2 或磷酸模拟 PLK1 T210D 可以部分挽救因细胞周期蛋白 A2 耗竭引起的 G2 期阻滞。细胞周期蛋白 A2 的细胞质存在受到 p21 的限制，尤其是在 DNA 损伤后。细胞周期蛋白 A2 在 DNA 复制过程中的染色质结合以及其他机制有助于 G2 期细胞周期蛋白 A2 定位的改变。我们没有发现这种机制涉及 G2 反馈环的证据，并表明细胞周期蛋白 A2 在 S/G2 转换时出现在细胞质中作为有丝分裂激酶激活的触发因素。
