Regulation of DNA Replication Licensing and Re-Replication by Cdt1.
Regulation of DNA Replication Licensing and Re-Replication by Cdt1.
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DOI：
10.3390/ijms22105195
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发表时间：
2021-05-14
影响因子：
5.6
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Zhang H
在真核细胞中，DNA复制许可被精确地调节，以确保S期基因组DNA复制的起始发生一次，并且对于每个有丝分裂细胞分裂仅发生一次。抑制DNA再复制的一个关键调节机制是Cdt 1的S期依赖性蛋白水解，Cdt 1是通过加载Mcm 2 -7复制解旋酶以在S期进行DNA复制来许可DNA复制起点的必需复制蛋白。Cdt 1的降解是由CRL 4 Cdt 2泛素E3连接酶介导的，这进一步需要Cdt 1在DNA合成过程中通过Cdt 1中的PIP盒结构域与增殖细胞核抗原（PCNA）结合。最近的研究发现，Cdt 2是CRL 4Cdt 2泛素E3连接酶的特异性亚基，靶向Cdt 1降解，也包含进化上保守的PIP盒样结构域，介导与PCNA的相互作用。这些研究结果表明，启动和延长DNA复制或DNA损伤诱导的修复合成提供了一种新的机制，Cdt 1和CRL 4Cdt 2都招募到三聚体PCNA钳包围复制的DNA链，以促进Cdt 1和CRL 4Cdt 2之间的相互作用。PCNA结合的Cdt 1与CRL 4Cdt 2的接近促进Cdt 1响应于DNA损伤或在DNA复制起始后的破坏，以防止细胞周期中的DNA再复制。CRL 4Cdt 2泛素E3连接酶还可以调节其他含PIP盒蛋白的降解，如CDK抑制剂p21和组蛋白甲基化酶Set 8，以通过在DNA复制和修复合成期间直接与PCNA相互作用来调节DNA复制许可、细胞周期进展、DNA修复和基因组稳定性。
In eukaryotic cells, DNA replication licensing is precisely regulated to ensure that the initiation of genomic DNA replication in S phase occurs once and only once for each mitotic cell division. A key regulatory mechanism by which DNA re-replication is suppressed is the S phase-dependent proteolysis of Cdt1, an essential replication protein for licensing DNA replication origins by loading the Mcm2-7 replication helicase for DNA duplication in S phase. Cdt1 degradation is mediated by CRL4Cdt2 ubiquitin E3 ligase, which further requires Cdt1 binding to proliferating cell nuclear antigen (PCNA) through a PIP box domain in Cdt1 during DNA synthesis. Recent studies found that Cdt2, the specific subunit of CRL4Cdt2 ubiquitin E3 ligase that targets Cdt1 for degradation, also contains an evolutionarily conserved PIP box-like domain that mediates the interaction with PCNA. These findings suggest that the initiation and elongation of DNA replication or DNA damage-induced repair synthesis provide a novel mechanism by which Cdt1 and CRL4Cdt2 are both recruited onto the trimeric PCNA clamp encircling the replicating DNA strands to promote the interaction between Cdt1 and CRL4Cdt2. The proximity of PCNA-bound Cdt1 to CRL4Cdt2 facilitates the destruction of Cdt1 in response to DNA damage or after DNA replication initiation to prevent DNA re-replication in the cell cycle. CRL4Cdt2 ubiquitin E3 ligase may also regulate the degradation of other PIP box-containing proteins, such as CDK inhibitor p21 and histone methylase Set8, to regulate DNA replication licensing, cell cycle progression, DNA repair, and genome stability by directly interacting with PCNA during DNA replication and repair synthesis.
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影响因子：
3.3
作者：
Bell SP;Labib K
通讯作者：
Labib K
影响因子：
3.7
作者：
de Munnik SA;Hoefsloot EH;Roukema J;Schoots J;Knoers NV;Brunner HG;Jackson AP;Bongers EM
通讯作者：
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影响因子：
16
作者：
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影响因子：
10.5
作者：
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通讯作者：
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影响因子：
9.8
作者：
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通讯作者：
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