Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
Nature. 2013 Sep 26;501(7468):564-8. doi: 10.1038/nature12471. Epub 2013 Aug 25.
Mammalian genomes contain several billion base pairs of DNA that are packaged in chromatin fibres. At selected gene loci, cohesin complexes have been proposed to arrange these fibres into higher-order structures, but how important this function is for determining overall chromosome architecture and how the process is regulated are not well understood. Using conditional mutagenesis in the mouse, here we show that depletion of the cohesin-associated protein Wapl stably locks cohesin on DNA, leads to clustering of cohesin in axial structures, and causes chromatin condensation in interphase chromosomes. These findings reveal that the stability of cohesin-DNA interactions is an important determinant of chromatin structure, and indicate that cohesin has an architectural role in interphase chromosome territories. Furthermore, we show that regulation of cohesin-DNA interactions by Wapl is important for embryonic development, expression of genes such as c-myc (also known as Myc), and cell cycle progression. In mitosis, Wapl-mediated release of cohesin from DNA is essential for proper chromosome segregation and protects cohesin from cleavage by the protease separase, thus enabling mitotic exit in the presence of functional cohesin complexes.
哺乳动物基因组包含数十亿个碱基对的 DNA，这些 DNA 被包装在染色质纤维中。在特定的基因座上，黏合蛋白复合物被提出可以将这些纤维排列成更高阶的结构，但这个功能对于确定整体染色体结构的重要性以及该过程是如何被调控的，目前还不是很清楚。在这里，我们使用小鼠的条件性突变，表明黏合蛋白相关蛋白 Wapl 的耗尽可稳定地将黏合蛋白锁定在 DNA 上，导致黏合蛋白在轴向结构中聚集，并导致有丝分裂间期染色体的染色质凝聚。这些发现揭示了黏合蛋白-DNA 相互作用的稳定性是染色质结构的一个重要决定因素，并表明黏合蛋白在有丝分裂间期染色体领域中具有结构作用。此外，我们还表明，Wapl 对黏合蛋白-DNA 相互作用的调控对于胚胎发育、c-myc（也称为 Myc）等基因的表达以及细胞周期进程都很重要。在有丝分裂中，Wapl 介导的从 DNA 上释放黏合蛋白对于正确的染色体分离是必不可少的，并且保护黏合蛋白免受蛋白酶 separase 的切割，从而使在功能性黏合蛋白复合物存在下能够完成有丝分裂退出。
