POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication.
POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication.
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DOI：
10.1016/j.molcel.2018.08.043
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发表时间：
2018-10-04
期刊：
影响因子：
16
通讯作者：
Boulton SJ
中科院分区：
文献类型：
--
作者：
Bellelli R;Belan O;Pye VE;Clement C;Maslen SL;Skehel JM;Cherepanov P;Almouzni G;Boulton SJ
表观遗传完整性的维持依赖于亲本组蛋白的协调再循环和分配以及DNA复制期间新合成的组蛋白的沉积。这一过程依赖于一个不良的组蛋白分子伴侣，重塑和结合蛋白的网络特征。在这里，我们牵连的POLE 3-POLE 4亚复合物的前导链聚合酶，Polε，在复制偶联核小体组装通过其选择性结合组蛋白H3-H4的能力。使用氢/氘交换质谱和物理作图，我们定义了POLE 3-POLE 4和组蛋白H3-H4之间相互作用所需的最小结构域。生化分析证实POLE 3-POLE 4是一种组蛋白伴侣，在体外促进四体形成和DNA超螺旋。在细胞中，POLE 3-POLE 4结合新合成的组蛋白和亲本组蛋白，其缺失阻碍解旋酶解旋和染色质PCNA卸载，并损害协调的亲本组蛋白保留和新组蛋白沉积。总的来说，我们的研究表明，POLE 3-POLE 4具有内在的H3-H4分子伴侣活性，这有利于忠实的核小体动力学在复制叉。哺乳动物POLE 3-POLE 4是一种真正的H2 A-H2 B组蛋白折叠复合物。POLE 3-POLE 4复合物在体外和体内与组蛋白H3-H4结合，POLE 3-POLE 4诱导四体形成和体外DNA超螺旋。报告称，哺乳动物POLE 3-POLE 4与组蛋白H3-H4结合，促进四体形成和DNA超螺旋，充当真正的组蛋白伴侣。与此一致，缺乏POLE 3/POLE 4的细胞表现出有缺陷的RPA积累和PCNA保留在染色质上，这是复制叉处有缺陷的染色质拆解/成熟的特征。
Maintenance of epigenetic integrity relies on coordinated recycling and partitioning of parental histones and deposition of newly synthesized histones during DNA replication. This process depends upon a poorly characterized network of histone chaperones, remodelers, and binding proteins. Here we implicate the POLE3-POLE4 subcomplex of the leading-strand polymerase, Polε, in replication-coupled nucleosome assembly through its ability to selectively bind to histones H3-H4. Using hydrogen/deuterium exchange mass spectrometry and physical mapping, we define minimal domains necessary for interaction between POLE3-POLE4 and histones H3-H4. Biochemical analyses establish that POLE3-POLE4 is a histone chaperone that promotes tetrasome formation and DNA supercoiling in vitro. In cells, POLE3-POLE4 binds both newly synthesized and parental histones, and its depletion hinders helicase unwinding and chromatin PCNA unloading and compromises coordinated parental histone retention and new histone deposition. Collectively, our study reveals that POLE3-POLE4 possesses intrinsic H3-H4 chaperone activity, which facilitates faithful nucleosome dynamics at the replication fork. Mammalian POLE3-POLE4 is a bona fide H2A-H2B histone fold complex The POLE3-POLE4 complex binds to histones H3-H4 in vitro and in vivo POLE3-POLE4 induces tetrasome formation and DNA supercoiling in vitro POLE3-POLE4 chaperone activity promotes chromatin integrity in mammalian cells Bellelli et al. report that mammalian POLE3-POLE4 binds to histones H3-H4 and promotes tetrasome formation and DNA supercoiling, acting as a bona fide histone chaperone. Consistent with this, cells lacking POLE3/POLE4 exhibit defective RPA accumulation and PCNA retention on chromatin, features of defective chromatin dismantling/maturation at the replication fork.
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