SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication.
SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication.
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DOI：
10.1038/ncomms10530
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发表时间：
2016-01-28
影响因子：
16.6
通讯作者：
Sørensen CS
中科院分区：
文献类型：
--
作者：
Walter D;Hoffmann S;Komseli ES;Rappsilber J;Gorgoulis V;Sørensen CS
维持基因组稳定性需要DNA在每个细胞周期精确复制一次。这被认为是通过限制复制起点许可，从而将每个复制起点的激发限制为每个细胞周期一次来实现的。CDC6是真核生物复制起点许可所必需的，然而，人们对CDC6活性在高等真核生物中是如何受到限制的知之甚少。在这里，我们报告说，SCF细胞周期蛋白F泛素连接酶复合物防止DNA再复制的靶向CDC6蛋白酶体降解后期在细胞周期。我们发现，CDC6和细胞周期蛋白F通过确定的序列基序，促进CDC6泛素化和降解相互作用。缺乏细胞周期蛋白F或表达稳定的突变体的CDC6促进再复制和基因组不稳定性的细胞缺乏CDT1抑制剂Geminin。总之，我们的工作揭示了一种新的SCF细胞周期蛋白F介导的机制，需要精确的每细胞周期复制一次。 为了确保基因组的稳定性，细胞需要将DNA复制限制在每个细胞周期一次。在这里，作者表明细胞周期蛋白F与许可因子CDC 6相互作用并靶向其降解，防止复制起点的重新启动。
Maintenance of genome stability requires that DNA is replicated precisely once per cell cycle. This is believed to be achieved by limiting replication origin licensing and thereby restricting the firing of each replication origin to once per cell cycle. CDC6 is essential for eukaryotic replication origin licensing, however, it is poorly understood how CDC6 activity is constrained in higher eukaryotes. Here we report that the SCFCyclin F ubiquitin ligase complex prevents DNA re-replication by targeting CDC6 for proteasomal degradation late in the cell cycle. We show that CDC6 and Cyclin F interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. Absence of Cyclin F or expression of a stable mutant of CDC6 promotes re-replication and genome instability in cells lacking the CDT1 inhibitor Geminin. Together, our work reveals a novel SCFCyclin F-mediated mechanism required for precise once per cell cycle replication. To ensure genome stability, cells need to restrict DNA replication to once per cell cycle. Here the authors show that Cyclin F interacts with and targets the licensing factor CDC6 for degradation, preventing re-firing of replication origins.