Cdt1 degradation to prevent DNA re-replication: conserved and non-conserved pathways.
Cdt1 degradation to prevent DNA re-replication: conserved and non-conserved pathways.
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DOI：
10.1186/1747-1028-2-18
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发表时间：
2007-06-12
期刊：
影响因子：
2.3
通讯作者：
Kipreos, Edward T
中科院分区：
文献类型：
--
作者：
Kim, Youngjo;Kipreos, Edward T
在真核生物中，DNA复制受到严格的调控，因此每个细胞周期只发生一次。防止过度DNA复制的机制集中在防止复制起点在同一细胞周期内被重复使用。这种调节涉及从DNA复制起始到复制前复合物（pre-RC）形成的时间分离。复制许可因子Cdt 1和Cdc 6将假定的复制解旋酶Mcm 2 -7复合物招募到M期或G1期晚期的复制起点以形成前RC。在裂殖酵母和后生动物中，Cdt 1许可因子在S期开始时通过泛素介导的蛋白水解被降解，以防止前RC的重新组装。在人类中，Cdt 1降解需要两种E3复合物，CUL 4-DDB 1CDT 2和SCFSkp 2。两种E3复合物使用不同的机制靶向Cdt 1泛素化。目前的数据表明，CUL 4-DDB 1CDT 2介导的Cdt 1降解是S期特异性的，而SCFSkp 2介导的Cdt 1降解发生在整个细胞周期。CUL 4-DDB 1 CDT 2 E3复合物降解Cdt 1是一种古老的进化途径，在真菌和后生动物中具有活性。相反，SCFSkp 2介导的Cdt 1降解似乎是最近才出现的。Skp 2在Cdt 1降解中的作用仅在人类中得到证实，并且该途径在酵母、无脊椎动物甚至其他脊椎动物中不保守。
In eukaryotes, DNA replication is strictly regulated so that it occurs only once per cell cycle. The mechanisms that prevent excessive DNA replication are focused on preventing replication origins from being reused within the same cell cycle. This regulation involves the temporal separation of the formation of the pre-replicative complex (pre-RC) from the initiation of DNA replication. The replication licensing factors Cdt1 and Cdc6 recruit the presumptive replicative helicase, the Mcm2-7 complex, to replication origins in late M or G1 phase to form pre-RCs. In fission yeast and metazoa, the Cdt1 licensing factor is degraded at the start of S phase by ubiquitin-mediated proteolysis to prevent the reassembly of pre-RCs. In humans, two E3 complexes, CUL4-DDB1CDT2 and SCFSkp2, are redundantly required for Cdt1 degradation. The two E3 complexes use distinct mechanisms to target Cdt1 ubiquitination. Current data suggests that CUL4-DDB1CDT2-mediated degradation of Cdt1 is S-phase specific, while SCFSkp2-mediated Cdt1 degradation occurs throughout the cell cycle. The degradation of Cdt1 by the CUL4-DDB1CDT2 E3 complex is an evolutionarily ancient pathway that is active in fungi and metazoa. In contrast, SCFSkp2-mediated Cdt1 degradation appears to have arisen relatively recently. A role for Skp2 in Cdt1 degradation has only been demonstrated in humans, and the pathway is not conserved in yeast, invertebrates, or even among other vertebrates.