Cdt1 revisited: complex and tight regulation during the cell cycle and consequences of deregulation in mammalian cells.
Cdt1 revisited: complex and tight regulation during the cell cycle and consequences of deregulation in mammalian cells.
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DOI：
10.1186/1747-1028-1-22
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发表时间：
2006-10-17
期刊：
影响因子：
2.3
通讯作者：
Fujita M
中科院分区：
文献类型：
--
作者：
Fujita M
在真核细胞中，基因组DNA的复制是从分布在多条染色体上的多个复制起点开始的。为了确保每个起始点在每个S期只被精确地激活一次，进化出了一个系统，其特征是在复制起始点周期性地组装和拆卸必要的复制前复合体（pre- rc）。预rc组装反应包括通过起源识别复合体（ORC）和两个基本因子CDC6和Cdt1将假定的复制解旋酶MCM2-7复合物装载到染色质上。真核细胞周期由周期蛋白依赖性激酶（cyclin-dependent kinase, Cdks）的周期性激活和失活驱动，pre- rc的组装只能发生在Cdk活性较低的时期，从有丝分裂晚期到G1期，在S、G2和M期不适当的重新组装受到抑制。最初认为，脊椎动物细胞S期后Cdt1功能的抑制是由于双联蛋白的结合，Cdt1-双联蛋白失衡导致的Cdt1功能亢进诱导了再复制。然而，最近的进展表明，除了双联蛋白外，Cdt1活性还受到两种其他机制的更严格调节：(1)Cdks磷酸化介导的功能性和scfskp2介导的蛋白水解调节；(2)由Cullin4-DDB1Cdt2泛素连接酶和PCNA介导的复制偶联蛋白水解，PCNA是一种真核生物滑动钳刺激复制DNA聚合酶。这种严格的调控意味着Cdt1的控制对哺乳动物细胞中DNA复制的调控尤为关键。事实上，即使没有再复制，Cdt1过表达也会引起染色体损伤。此外，在正常人类细胞中，失调的Cdt1诱导染色体不稳定。由于Cdt1在癌细胞中过度表达，这可能是导致癌变的一种新的分子机制。本文就Cdt1在哺乳动物细胞中的功能和调控作一综述。
In eukaryotic cells, replication of genomic DNA initiates from multiple replication origins distributed on multiple chromosomes. To ensure that each origin is activated precisely only once during each S phase, a system has evolved which features periodic assembly and disassembly of essential pre-replication complexes (pre-RCs) at replication origins. The pre-RC assembly reaction involves the loading of a presumptive replicative helicase, the MCM2-7 complexes, onto chromatin by the origin recognition complex (ORC) and two essential factors, CDC6 and Cdt1. The eukaryotic cell cycle is driven by the periodic activation and inactivation of cyclin-dependent kinases (Cdks) and assembly of pre-RCs can only occur during the low Cdk activity period from late mitosis through G1 phase, with inappropriate re-assembly suppressed during S, G2, and M phases. It was originally suggested that inhibition of Cdt1 function after S phase in vertebrate cells is due to geminin binding and that Cdt1 hyperfunction resulting from Cdt1-geminin imbalance induces re-replication. However, recent progress has revealed that Cdt1 activity is more strictly regulated by two other mechanisms in addition to geminin: (1) functional and SCFSkp2-mediated proteolytic regulation through phosphorylation by Cdks; and (2) replication-coupled proteolysis mediated by the Cullin4-DDB1Cdt2 ubiquitin ligase and PCNA, an eukaryotic sliding clamp stimulating replicative DNA polymerases. The tight regulation implies that Cdt1 control is especially critical for the regulation of DNA replication in mammalian cells. Indeed, Cdt1 overexpression evokes chromosomal damage even without re-replication. Furthermore, deregulated Cdt1 induces chromosomal instability in normal human cells. Since Cdt1 is overexpressed in cancer cells, this could be a new molecular mechanism leading to carcinogenesis. In this review, recent insights into Cdt1 function and regulation in mammalian cells are discussed.
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