Multisite phosphorylation by Cdk1 initiates delayed negative feedback to control mitotic transcription.
Multisite phosphorylation by Cdk1 initiates delayed negative feedback to control mitotic transcription.
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DOI：
10.1016/j.cub.2021.11.001
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发表时间：
2022-01-10
期刊：
影响因子：
--
通讯作者：
Morgan DO
中科院分区：
文献类型：
--
作者：
Asfaha JB;Örd M;Carlson CR;Faustova I;Loog M;Morgan DO
细胞周期的进展是由细胞周期蛋白依赖性激酶(CDK)底物的磷酸化驱动的。底物磷酸化的顺序在一定程度上取决于细胞周期中CDK活性的普遍上升，以及底物对接到相关的细胞周期蛋白和CKS亚基上的位点的变化。许多底物在多个位置被修饰，以提供更复杂的调节。在这里，我们描述了一种优雅的基于Ndd1多位点磷酸化的调节电路，Ndd1是有丝分裂进程所需的萌芽酵母基因的转录辅助激活因子。当细胞进入有丝分裂时，CDK1对Ndd1的磷酸化可以促进有丝分裂周期蛋白(CLB2)基因的转录，从而产生正反馈。与这些发现一致，我们表明低活性的CDK1促进了有丝分裂进入时CLB2的表达。然而，我们也发现，当高CDK1活性在有丝分裂停滞中积累时，CLB2的表达被抑制。抑制伴随着Ndd1的降解，我们提出的证据表明，降解是由高有丝分裂的CDK1-Clb2活性引起的多位点Ndd1磷酸化引发的。通过Clb2-CDK1-Cks1完成Ndd1的磷酸化需要Cks1的磷酸苏氨酸结合部位，以及最近发现的周期蛋白Clb2上的磷酸盐结合口袋。因此，我们认为，CDK1的初始磷酸化使Ndd1在促进降解的次优位置延迟二次磷酸化。总之，我们的结果表明，有丝分裂CDK1活性的升高作用于Ndd1上的多个磷酸化位点，首先触发快速正反馈，然后促进延迟的负反馈，导致有丝分裂基因表达的脉冲。Asfaha等人。证明蛋白激酶CDK1通过促进转录共激活因子Ndd1的降解来限制有丝分裂基因的表达。Ndd1的降解是由复杂的磷酸化事件模式触发的，该模式部分依赖于与CDK1相关的Cyclin和Cks亚基与磷酸盐的结合。
Cell-cycle progression is driven by the phosphorylation of cyclin-dependent kinase (Cdk) substrates. The order of substrate phosphorylation depends in part on the general rise in Cdk activity during the cell cycle, together with variations in substrate docking to sites on associated cyclin and Cks subunits. Many substrates are modified at multiple sites to provide more complex regulation. Here, we describe an elegant regulatory circuit based on multisite phosphorylation of Ndd1, a transcriptional co-activator of budding yeast genes required for mitotic progression. As cells enter mitosis, Ndd1 phosphorylation by Cdk1 is known to promote mitotic cyclin (CLB2) gene transcription, resulting in positive feedback. Consistent with these findings, we show that low Cdk1 activity promotes CLB2 expression at mitotic entry. We also find, however, that when high Cdk1 activity accumulates in a mitotic arrest, CLB2 expression is inhibited. Inhibition is accompanied by Ndd1 degradation, and we present evidence that degradation is triggered by multisite Ndd1 phosphorylation by high mitotic Cdk1-Clb2 activity. Complete Ndd1 phosphorylation by Clb2-Cdk1-Cks1 requires the phosphothreonine-binding site of Cks1, as well as a recently identified phosphate-binding pocket on the cyclin Clb2. We therefore propose that initial phosphorylation by Cdk1 primes Ndd1 for delayed secondary phosphorylation at suboptimal sites that promote degradation. Together, our results suggest that rising levels of mitotic Cdk1 activity act at multiple phosphorylation sites on Ndd1, first triggering rapid positive feedback and then promoting delayed negative feedback, resulting in a pulse of mitotic gene expression. Asfaha et al. demonstrate that the protein kinase Cdk1 limits mitotic gene expression by promoting degradation of the transcriptional co-activator Ndd1. Ndd1 degradation is triggered by a complex pattern of phosphorylation events that depend in part on phosphate binding by the cyclin and Cks subunits associated with Cdk1.
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DOI：
10.1083/jcb.201303033
发表时间：
2013-09-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Vernieri C;Chiroli E;Francia V;Gross F;Ciliberto A
通讯作者：
Ciliberto A
影响因子：
16.8
作者：
Koivomaegi, Mardo;Oerd, Mihkel;Iofik, Anna;Valk, Ervin;Venta, Rainis;Faustova, Ilona;Kivi, Rait;Balog, Eva Rose M.;Rubin, Seth M.;Loog, Mart
通讯作者：
Loog, Mart
影响因子：
5.3
作者：
Hsiung, YG;Chang, HC;Wittenberg, C
通讯作者：
Wittenberg, C
影响因子：
4.8
作者：
Goda, T;Ishii, T;Kobayashi, H
通讯作者：
Kobayashi, H
影响因子：
8.8
作者：
Ord, Mihkel;Puss, Kait Kaarel;Loog, Mart
通讯作者：
Loog, Mart