Cyclin A2/cyclin-dependent kinase 1-dependent phosphorylation of Top2a is required for S phase entry during retinal development in zebrafish
Cyclin A2/cyclin-dependent kinase 1-dependent phosphorylation of Top2a is required for S phase entry during retinal development in zebrafish
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斑马鱼视网膜发育过程中，细胞周期蛋白 A2/细胞周期蛋白依赖性激酶 1 依赖性 Top2a 磷酸化是进入 S 期所必需的
DOI：
10.1016/j.jgg.2021.01.001
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发表时间：
2021-01-20
影响因子：
5.9
通讯作者：
Cao, Ying
中科院分区：
文献类型：
--
作者：
Jin, Miaomiao;Li, Jingyu;Cao, Ying
细胞周期蛋白依赖性激酶1（Cyclin-dependent kinase 1，CDK 1）在细胞周期调控中起重要作用。然而，由于小鼠Cdk 1胚胎死亡早，CDK 1在调节细胞周期和胚胎发育中的作用仍不清楚。在这里，我们发现，斑马鱼cdk 1（-/-）胚胎表现出严重的小眼症伴随着多重缺陷，在S期进入，M期进展，细胞分化，但不是在运动间核迁移。我们确定Top 2a作为一个潜在的下游目标和细胞周期蛋白A2和细胞周期蛋白B1作为合作伙伴的Cdk 1在细胞周期调控，通过计算机分析。虽然细胞周期蛋白A2或Top 2a的耗竭导致斑马鱼视网膜细胞S期进入减少，但细胞周期蛋白B1的耗竭导致M期停滞。此外，磷酸化的Top 2a在丝氨酸1213（S1213）几乎被取消在cdk 1和ccna 2突变体，但不是在ccnb 1突变体。此外，TOP2 AS 1213 D（人TOP 2A的磷酸化模拟形式）的过表达挽救了cdk 1（-/-）和ccna 2（-/-）胚胎中的S期进入并减轻了小眼缺陷。综上所述，我们的数据表明，Cdk 1与细胞周期蛋白A2相互作用，部分通过Top 2a磷酸化调节S期进入，并与细胞周期蛋白B1相互作用，调节M期进程。版权所有（C）2021，作者。中国科学院遗传与发育生物学研究所、中国遗传学会。由爱思唯尔有限公司和科学出版社出版。
Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation. However, as mouse Cdk1 embryos die early, the role of CDK1 in regulating the cell cycle and embryo development remains unclear. Here, we showed that zebrafish cdk1(-/-) embryos exhibit severe microphthalmia accompanied by multiple defects in S phase entry, M phase progression, and cell differentiation but not in interkinetic nuclear migration. We identified Top2a as a potential downstream target and cyclin A2 and cyclin B1 as partners of Cdk1 in cell cycle regulation via an in silico analysis. While depletion of either cyclin A2 or Top2a led to the decreased S phase entry in zebrafish retinal cells, the depletion of cyclin B1 led to M phase arrest. Moreover, phosphorylation of Top2a at serine 1213 (S1213) was nearly abolished in both cdk1 and ccna2 mutants, but not in ccnb1 mutants. Furthermore, overexpression of TOP2AS1213D, the phosphomimetic form of human TOP2A, rescued S phase entry and alleviated the microphthalmia defects in both cdk1(-/-) and ccna2(-/-) embryos. Taken together, our data suggest that Cdk1 interacts with cyclin A2 to regulate S phase entry partially through Top2a phosphorylation and interacts with cyclin B1 to regulate M phase progression. Copyright (C) 2021, The Authors. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press.