Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.
Department of Chromosome Science, National Institute of Genetics, Shizuoka, Japan.
Nat Commun. 2024 Nov 2;15(1):9485. doi: 10.1038/s41467-024-53187-4.
In chromatin replication, faithful recycling of histones from parental DNA to replicated strands is essential for maintaining epigenetic information across generations. A previous experiment has revealed that disrupting interactions between the N-terminal tail of Mcm2, a subunit in DNA replication machinery, and a histone H3/H4 tetramer perturb the recycling. However, the molecular pathways and the factors that regulate the ratio recycled to each strand and the destination location are yet to be revealed. Here, we performed molecular dynamics simulations of yeast DNA replication machinery, an H3/H4 tetramer, and replicated DNA strands. The simulations demonstrated that histones are recycled via Cdc45-mediated and unmediated pathways without histone chaperones, as our in vitro biochemical assays supported. Also, RPA binding regulated the ratio recycled to each strand, whereas DNA bending by Pol ε modulated the destination location. Together, the simulations provided testable hypotheses, which are vital for elucidating the molecular mechanisms of histone recycling.
在染色质复制中，将组蛋白从亲本 DNA 忠实回收至复制链对于跨代维持表观遗传信息至关重要。先前的实验表明，破坏 DNA 复制机制亚基 Mcm2 的 N 端尾巴与组蛋白 H3/H4 四聚体之间的相互作用会扰乱回收。然而，分子途径和调节每个链回收比例以及目的地位置的因素尚未揭示。在这里，我们对酵母 DNA 复制机制、H3/H4 四聚体和复制 DNA 链进行了分子动力学模拟。模拟表明，组蛋白通过 Cdc45 介导和非介导途径回收，而无需组蛋白伴侣，这得到了我们的体外生化测定的支持。此外，RPA 结合调节每个链的回收比例，而 Polε 引起的 DNA 弯曲调节目的地位置。总之，模拟提供了可测试的假设，对于阐明组蛋白回收的分子机制至关重要。
