Division of Biological Sciences, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan.
Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo Kyoto 606-8501, Japan.
Cell Rep. 2021 Apr 27;35(4):108999. doi: 10.1016/j.celrep.2021.108999.
The ring-shaped cohesin complex topologically binds to DNA to establish sister chromatid cohesion. This topological binding creates a structural obstacle to genome-wide chromosomal events, such as replication. Here, we examine how conformational changes in cohesin circumvent being an obstacle in human cells. We show that ATP hydrolysis-driven head disengagement, leading to the structural maintenance of chromosome (SMC) ring opening, is essential for the progression of DNA replication. Closure of the SMC ring stalls replication in a checkpoint-independent manner. The SMC ring opening also facilitates sister chromatid resolution and chromosome segregation in mitosis. Single-molecule analyses reveal that forced closure of the SMC ring suppresses the translocation of cohesin on DNA as well as the formation of stable DNA loops. Our results suggest that the ATP hydrolysis-driven SMC ring opening makes topologically bound cohesin dynamic on DNA to achieve replication-dependent cohesion in the S phase and to resolve cohesion in mitosis. Thus, the SMC ring opening could be a fundamental mechanism to modulate both cohesion and higher-order genome structure.
环型黏连复合物通过拓扑绑定 DNA 来建立姐妹染色单体黏合。这种拓扑结合为全基因组染色体事件（如复制）创造了结构障碍。在这里，我们研究了黏合复合物的构象变化如何规避成为人类细胞中的障碍。我们表明，ATP 水解驱动的头部脱离，导致结构维持染色体（SMC）环打开，对于 DNA 复制的进行是必不可少的。SMC 环的闭合以独立于检查点的方式阻止复制。SMC 环的打开也有助于有丝分裂中姐妹染色单体的分离和染色体分离。单分子分析表明，SMC 环的强制闭合抑制了黏合蛋白在 DNA 上的易位以及稳定 DNA 环的形成。我们的结果表明，SMC 环的 ATP 水解驱动打开使拓扑绑定的黏合蛋白在 DNA 上具有动态性，从而在 S 期实现复制依赖性黏合，并在有丝分裂中解决黏合。因此，SMC 环的打开可能是调节黏合和更高阶基因组结构的基本机制。
