Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms
Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms
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DOI：
10.1038/35082600
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发表时间：
2001-06-28
期刊：
影响因子：
64.8
通讯作者：
Li, JJ
中科院分区：
文献类型：
--
作者：
Nguyen, VQ;Co, C;Li, JJ
遗传信息的稳定传递要求生物体的整个基因组在每个细胞周期中精确地复制一次且仅一次。在真核生物中，这种复制起始于分布在基因组上的数百到数千个复制起点，在每个细胞周期内，必须阻止每个起点再次起始DNA复制。细胞如何防止再次起始一直是细胞生物学中一个长期存在的问题。在一些真核生物中，细胞周期蛋白依赖性激酶（CDKs）被认为与促进对再次起始的阻断有关，但它们究竟如何发挥这一功能尚不清楚。在此我们表明，酿酒酵母中的B型细胞周期蛋白依赖性激酶通过多种重叠机制防止再次起始，包括对起始识别复合物（ORC）的磷酸化、Cdc6活性的下调以及Mcm2 - 7复合物的核排斥。只有当所有这三种抑制途径都被破坏时，起点才会在G2/M期细胞中再次起始DNA复制。这些研究表明，这三种独立的调控机制中的每一种在功能上都很重要。
The stable propagation of genetic information requires that the entire genome of an organism be faithfully replicated once and only once each cell cycle. In eukaryotes, this replication is initiated at hundreds to thousands of replication origins distributed over the genome, each of which must be prohibited from re-initiating DNA replication within every cell cycle. How cells prevent reinitiation has been a long-standing question in cell biology. In several eukaryotes, cyclin-dependent kinases (CDKs) have been implicated in promoting the block to re-initiation(1), but exactly how they perform this function is unclear. Here we show that B-type CDKs in Saccharomyces cerevisiae prevent re-initiation through multiple overlapping mechanisms, including phosphorylation of the origin recognition complex (ORC), downregulation of Cdc6 activity, and nuclear exclusion of the Mcm2-7 complex. Only when all three inhibitory pathways are disrupted do origins re-initiate DNA replication in G2/M cells. These studies show that each of these three independent mechanisms of regulation is functionally important.