Insights into the Initiation of Eukaryotic DNA Replication
Insights into the Initiation of Eukaryotic DNA Replication
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DOI：
10.1080/19491034.2015.1115938
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发表时间：
2015-11-01
期刊：
影响因子：
3.7
通讯作者：
Kaplan, Daniel L.
中科院分区：
文献类型：
--
作者：
Bruck, Irina;Perez-Arnaiz, Patricia;Kaplan, Daniel L.
DNA复制的起始是真核细胞中高度调控的事件，以确保整个基因组在S期复制一次且仅复制一次。真核生物DNA复制起始的细胞调控的主要目标是复制叉解旋酶的组装和激活，该11亚基组装使DNA在复制叉处解旋。复制叉解旋酶，称为Cdc 45-Mcm 2 -7和GINS的CMG，在S期从组分Cdc 45、Mcm 2 -7和GINS蛋白组装。CMG复制叉解旋酶在S期的组装和激活由2种S期特异性激酶CDK和DDK控制。CDK刺激Sld 2、Sld 3和Dpb 11，3个起始因子之间的相互作用，每个起始因子都是DNA复制起始所需的。另一方面，DDK磷酸化Mcm 2 -7复合物的Mcm 2、Mcm 4和Mcm 6亚基。Sld 3以依赖于DDK的方式将Cdc 45招募到Mcm 2 -7，最近的工作表明Sld 3直接与Mcm 2 -7结合，也与单链DNA结合。此外，最近的工作表明，Sld 3及其人类同源物Treslin实质上刺激Mcm 2的DDK磷酸化。这些数据表明，起始因子Sld 3/Treslin协调真核生物复制叉解旋酶的组装和激活，通过招募Cdc 45到Mcm 2 -7，刺激Mcm 2的DDK磷酸化，并直接结合到单链DNA作为起点被熔化。
The initiation of DNA replication is a highly regulated event in eukaryotic cells to ensure that the entire genome is copied once and only once during S phase. The primary target of cellular regulation of eukaryotic DNA replication initiation is the assembly and activation of the replication fork helicase, the 11-subunit assembly that unwinds DNA at a replication fork. The replication fork helicase, called CMG for Cdc45-Mcm2-7, and GINS, assembles in S phase from the constituent Cdc45, Mcm2-7, and GINS proteins. The assembly and activation of the CMG replication fork helicase during S phase is governed by 2 S-phase specific kinases, CDK and DDK. CDK stimulates the interaction between Sld2, Sld3, and Dpb11, 3 initiation factors that are each required for the initiation of DNA replication. DDK, on the other hand, phosphorylates the Mcm2, Mcm4, and Mcm6 subunits of the Mcm2-7 complex. Sld3 recruits Cdc45 to Mcm2-7 in a manner that depends on DDK, and recent work suggests that Sld3 binds directly to Mcm2-7 and also to single-stranded DNA. Furthermore, recent work demonstrates that Sld3 and its human homolog Treslin substantially stimulate DDK phosphorylation of Mcm2. These data suggest that the initiation factor Sld3/Treslin coordinates the assembly and activation of the eukaryotic replication fork helicase by recruiting Cdc45 to Mcm2-7, stimulating DDK phosphorylation of Mcm2, and binding directly to single-stranded DNA as the origin is melted.