In eukaryotes, DNA replication constitutes a complex process whereby multiple origins are stochastically fired, and from which the replication machinery proceeds along chromosomes to achieve the faithful synthesis of two identical copies of the genome during the S phase of the cell cycle. Experimental evidence shows a functional correlation between the dynamics of replication and the spatial organization of the genome inside cell nuclei, suggesting that the process of replicating DNA may impact chromosome folding. However, the theoretical and mechanistic bases of such a hypothesis remain elusive. To address that question, we propose a quantitative, minimal framework that integrates the dynamics of replication along a polymer chain by accounting explicitly for the progression of the replication machinery and the resulting formation of sister chromatids. By systematically characterizing the 3D structural consequences of replication, and of possible interactions between active replication machineries, we show that the formation of transient loops may potentially impact chromosome organization across multiple temporal and spatial scales, from the level of individual origins to that of the global polymer chain. Comparison with available microscopy and chromosome conformation capture data in yeast suggests that a replication-dependent loop extrusion process may be acting in vivo, and may shape chromosomes as loose polymer bottle brushes during the S phase. Lastly, we explore the postreplication relative organization of sister chromatids and demonstrate the emergence of catenations and intertwined structures, which are regulated by the density of fired origins.

中文翻译：

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DNA 复制和聚合物链复制在空间和时间上重塑基因组


在真核生物中，DNA 复制构成了一个复杂的过程，其中多个起点随机触发，复制机制从该过程沿着染色体进行，以在细胞周期的 S 期实现两个相同基因组拷贝的忠实合成。实验证据表明，复制动力学与细胞核内基因组的空间组织之间存在功能相关性，表明复制 DNA 的过程可能会影响染色体折叠。然而，这种假设的理论和机械基础仍然难以捉摸。为了解决这个问题，我们提出了一个定量的最小框架，该框架通过明确解释复制机制的进展和由此产生的姐妹染色单体的形成，整合了沿聚合物链的复制动力学。通过系统地表征复制的 3D 结构后果以及活性复制机制之间可能的相互作用，我们表明瞬时环的形成可能会在多个时间和空间尺度上影响染色体组织，从单个起源的水平到整体聚合物链的水平。与可用的显微镜和酵母中的染色体构象捕获数据进行比较表明，复制依赖性的环挤出过程可能在体内起作用 ，并且可能在 S 期将染色体塑造成松散的聚合物瓶刷。最后，我们探讨了姐妹染色单体的复制后相对组织，并证明了串联和交织结构的出现，它们受发射起点密度的调节。