The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands.
The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands.
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DOI：
10.1016/j.molcel.2018.09.001
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发表时间：
2018-10-04
期刊：
影响因子：
16
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Gan H;Serra-Cardona A;Hua X;Zhou H;Labib K;Yu C;Zhang Z
虽然对于表观遗传是必要的，但对含有表观遗传修饰的亲本组蛋白（H3-H4）2四聚体向复制DNA链的转移知之甚少。在这里，我们发现Mcm 2-Ctf 4-Polα轴促进亲本（H3-H4）2四聚体在复制叉处转移到滞后链DNA。CMG（Cdc 45-MCM-GINS）DNA解旋酶的Mcm 2亚基的保守组蛋白结合结构域沿着前导链模板移位沿着，突变该结构域导致亲本（H3-H4）2在前导链上显著富集，这是由于亲本（H3-H4）2向滞后链的转移受损。在Ctf 4和Polα引发酶突变体中观察到类似的效应，这些突变体破坏了CMG解旋酶与位于滞后链模板上的Polα的连接。我们的研究结果支持了一个模型，即父母（H3-H4）2复合物从核小体的DNA解旋在复制叉被转移的CMG-Ctf 4-Polα复合物的滞后链DNA的核小体组装在原来的位置。亲本组蛋白H3-H4四聚体如何转移到复制DNA链中进行表观遗传仍然是未知的。Gan等人表明，亲本H3-H4四聚体与Mcm 2结合，Mcm 2沿着前导链模板沿着移动，然后通过Mcm 2-Ctf 4-Polα复合物转移到滞后链，进行核小体组装。
Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4)2 tetramers that contain epigenetic modifications to replicating DNA strands is poorly understood. Here, we show that the Mcm2-Ctf4-Polα axis facilitates the transfer of parental (H3-H4)2 tetramers to lagging-strand DNA at replication forks. Mutating the conserved histone-binding domain of the Mcm2 subunit of the CMG (Cdc45-MCM-GINS) DNA helicase, which translocates along the leading-strand template, results in a marked enrichment of parental (H3-H4)2 on leading-strand, due to the impairment of the transfer of parental (H3-H4)2 to lagging strands. Similar effects are observed in Ctf4 and Polα primase mutants that disrupt the connection of the CMG helicase to Polα that resides on lagging strand template. Our results support a model whereby parental (H3-H4)2 complexes displaced from nucleosomes by DNA unwinding at replication forks are transferred by the CMG-Ctf4-Polα complex to lagging-strand DNA for nucleosome assembly at the original location. How parental histone H3-H4 tetramers are transferred to replicating DNA strands for epigenetic inheritance remains largely unknown. Gan and al. show that parental H3-H4 tetramers bind to Mcm2, which travel along the leading-strand template, and are then transferred to the lagging strand by the Mcm2-Ctf4-Polα complex for nucleosome assembly.
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