Precise control of sister chromatid separation during mitosis is pivotal to maintaining genomic integrity. Yet, the regulatory mechanisms involved are not well understood. Remarkably, we discovered that linker histone H1 phosphorylated at S/T18 decorated the inter-chromatid axial DNA on mitotic chromosomes. Sister chromatid resolution during mitosis required the eviction of such H1S/T18ph by the chaperone SET, with this process being independent of and most likely downstream of arm-cohesin dissociation. SET also directed the disassembly of Shugoshins in a polo-like kinase 1-augmented manner, aiding centromere resolution. SET ablation compromised mitotic fidelity as evidenced by unresolved sister chromatids with marked accumulation of H1S/T18ph and centromeric Shugoshin. Thus, chaperone-assisted eviction of linker histones and Shugoshins is a fundamental step in mammalian mitotic progression. Our findings also elucidate the functional implications of the decades-old observation of mitotic linker histone phosphorylation, serving as a paradigm to explore the role of linker histones in bio-signaling processes.

有丝分裂期间精确控制姐妹染色单体分离对于维持基因组完整性至关重要。然而，所涉及的监管机制尚不清楚。值得注意的是，我们发现在 S/T18 处磷酸化的接头组蛋白 H1 修饰了有丝分裂染色体上的染色单体间轴向 DNA。有丝分裂期间的姐妹染色单体解析需要伴侣 SET 驱逐此类 H1S/T18ph，该过程独立于臂粘连蛋白解离，并且很可能位于臂粘连蛋白解离的下游。 SET 还以类似 polo 激酶 1 增强的方式指导 Shugoshins 的分解，帮助着丝粒解析。 SET 消融损害了有丝分裂的保真度，这一点可以通过未解析的姐妹染色单体以及 H1S/T18ph 和着丝粒 Shugoshin 的显着积累来证明。因此，分子伴侣辅助的连接组蛋白和 Shugoshins 的驱逐是哺乳动物有丝分裂进展的基本步骤。我们的研究结果还阐明了几十年来对有丝分裂接头组蛋白磷酸化的观察的功能意义，作为探索接头组蛋白在生物信号传导过程中的作用的范例。