CUL4B promotes replication licensing by up-regulating the CDK2-CDC6 cascade.
CUL4B promotes replication licensing by up-regulating the CDK2-CDC6 cascade.
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DOI：
10.1083/jcb.201206065
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发表时间：
2013-03-18
期刊：
影响因子：
--
通讯作者：
Gong Y
中科院分区：
文献类型：
--
作者：
Zou Y;Mi J;Wang W;Lu J;Zhao W;Liu Z;Hu H;Yang Y;Gao X;Jiang B;Shao C;Gong Y
CUL4B通过抑制miR-372和miR-373上调CDK2，导致CDC6磷酸化和稳定化增加，从而促进复制许可。库林环泛素连接酶(CRL)参与多种细胞过程的调控，包括细胞周期进程。X连锁的CUL4B是cullin家族的成员之一，它的突变会导致人类的智力低下和其他发育异常。在杂合子中，CUL4B缺乏的细胞在体内被严格挑选出来。在这里，我们报告了CUL4B在复制许可调节中的作用。值得注意的是，复制中的许可因子CDC6受到CUL4B的正调控，并有助于将MCM2装载到染色质中。CUL4B对CDC6的正向调节依赖于CDK2，CDK2使CDC6磷酸化，保护其免受APCCDH1介导的降解。因此，CDK2除了是细胞从静止状态重新进入细胞周期所必需的外，还参与了周期细胞G1期的复制前复合体的组装。有趣的是，CUL4B上调CDK2是通过抑制靶向CDK2的miR-372和miR-373实现的。因此，我们的发现在DNA复制许可的调控中建立了CUL4B-CDK2-CDC6级联反应。
CUL4B up-regulates CDK2 by repressing miR-372 and miR-373, leading to increased phosphorylation and stabilization of CDC6, thus promoting replication licensing. Cullin-RING ubiquitin ligases (CRLs) participate in the regulation of diverse cellular processes including cell cycle progression. Mutations in the X-linked CUL4B, a member of the cullin family, cause mental retardation and other developmental abnormalities in humans. Cells that are deficient in CUL4B are severely selected against in vivo in heterozygotes. Here we report a role of CUL4B in the regulation of replication licensing. Strikingly, CDC6, the licensing factor in replication, was positively regulated by CUL4B and contributed to the loading of MCM2 to chromatin. The positive regulation of CDC6 by CUL4B depends on CDK2, which phosphorylates CDC6, protecting it from APCCDH1-mediated degradation. Thus, aside being required for cell cycle reentry from quiescence, CDK2 also contributes to pre-replication complex assembly in G1 phase of cycling cells. Interestingly, the up-regulation of CDK2 by CUL4B is achieved via the repression of miR-372 and miR-373, which target CDK2. Our findings thus establish a CUL4B–CDK2–CDC6 cascade in the regulation of DNA replication licensing.
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