Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
Division of Pre-Clinical Innovation, NCATS, National Institutes of Health, Rockville, MD 20850, USA.
Mol Cell. 2021 Dec 16;81(24):5007-5024.e9. doi: 10.1016/j.molcel.2021.10.015. Epub 2021 Nov 11.
As cells enter mitosis, chromatin compacts to facilitate chromosome segregation yet remains transcribed. Transcription supercoils DNA to levels that can impede further progression of RNA polymerase II (RNAPII) unless it is removed by DNA topoisomerase 1 (TOP1). Using ChIP-seq on mitotic cells, we found that TOP1 is required for RNAPII translocation along genes. The stimulation of TOP1 activity by RNAPII during elongation allowed RNAPII clearance from genes in prometaphase and enabled chromosomal segregation. Disruption of the TOP1-RNAPII interaction impaired RNAPII spiking at promoters and triggered defects in the post-mitotic transcription program. This program includes factors necessary for cell growth, and cells with impaired TOP1-RNAPII interaction are more sensitive to inhibitors of mTOR signaling. We conclude that TOP1 is necessary for assisting transcription during mitosis with consequences for growth and gene expression long after mitosis is completed. In this sense, TOP1 ensures that cellular memory is preserved in subsequent generations.
当细胞进入有丝分裂时，染色质会紧缩以促进染色体分离，但仍保持转录。转录使 DNA 超螺旋化到阻碍 RNA 聚合酶 II（RNAPII）进一步前进的程度，除非它被 DNA 拓扑异构酶 1（TOP1）去除。通过对有丝分裂细胞进行 ChIP-seq 分析，我们发现 TOP1 是 RNAPII 在基因上转运所必需的。在延伸过程中，RNAPII 对 TOP1 活性的刺激允许 RNAPII 在前期从基因中清除，并使染色体分离。TOP1-RNAPII 相互作用的破坏会干扰启动子处的 RNAPII 尖峰，并引发有丝分裂后转录程序的缺陷。该程序包括细胞生长所必需的因素，而 TOP1-RNAPII 相互作用受损的细胞对 mTOR 信号抑制剂更敏感。我们得出结论，TOP1 在有丝分裂期间协助转录是必要的，这对有丝分裂完成后很长一段时间的生长和基因表达都有影响。从这个意义上说，TOP1 确保了细胞记忆在后代中得以保留。
