Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA.
Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA.
J Biol Chem. 2021 Sep;297(3):101026. doi: 10.1016/j.jbc.2021.101026. Epub 2021 Jul 30.
Sister chromatid cohesion (SCC), the pairing of sister chromatids after DNA replication until mitosis, is established by loading of the cohesin complex on newly replicated chromatids. Cohesin must then be maintained until mitosis to prevent segregation defects and aneuploidy. However, how SCC is established and maintained until mitosis remains incompletely understood, and emerging evidence suggests that replication stress may lead to premature SCC loss. Here, we report that the ssDNA-binding protein CTC1-STN1-TEN1 (CST) aids in SCC. CST primarily functions in telomere length regulation but also has known roles in replication restart and DNA repair. After depletion of CST subunits, we observed an increase in the complete loss of SCC. In addition, we determined that CST associates with the cohesin complex. Unexpectedly, we did not find evidence of altered cohesin loading or mitotic progression in the absence of CST; however, we did find that treatment with various replication inhibitors increased the association between CST and cohesin. Because replication stress was recently shown to induce SCC loss, we hypothesized that CST may be required to maintain or remodel SCC after DNA replication fork stalling. In agreement with this idea, SCC loss was greatly increased in CST-depleted cells after exogenous replication stress. Based on our findings, we propose that CST aids in the maintenance of SCC at stalled replication forks to prevent premature cohesion loss.
姐妹染色单体黏合（Sister chromatid cohesion，SCC），即在 DNA 复制后直到有丝分裂前，姐妹染色单体的配对，是通过将黏合复合物加载到新复制的染色单体上而建立的。黏合复合物必须在有丝分裂前维持，以防止分离缺陷和非整倍体。然而，SCC 是如何建立和维持到有丝分裂仍然不完全清楚，新出现的证据表明复制应激可能导致 SCC 过早丢失。在这里，我们报告 ssDNA 结合蛋白 CTC1-STN1-TEN1（CST）有助于 SCC 的建立。CST 主要在端粒长度调节中发挥作用，但也在复制起始和 DNA 修复中具有已知作用。在 CST 亚基耗竭后，我们观察到 SCC 完全丢失的增加。此外，我们确定 CST 与黏合复合物相关联。出乎意料的是，我们在没有 CST 的情况下没有发现改变的黏合复合物加载或有丝分裂进展的证据；然而，我们确实发现，用各种复制抑制剂处理会增加 CST 和黏合复合物之间的关联。由于最近表明复制应激会诱导 SCC 丢失，我们假设 CST 可能在 DNA 复制叉停滞后维持或重塑 SCC。与这个想法一致，在外源复制应激后 CST 耗竭细胞中的 SCC 丢失大大增加。基于我们的发现，我们提出 CST 有助于在停滞的复制叉处维持 SCC，以防止过早的黏合丧失。
