Chromosome Segregation Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Chromosome Replication Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Cell. 2023 Feb 16;186(4):837-849.e11. doi: 10.1016/j.cell.2022.12.044. Epub 2023 Jan 23.
Concomitant with DNA replication, the chromosomal cohesin complex establishes cohesion between newly replicated sister chromatids. Cohesion establishment requires acetylation of conserved cohesin lysine residues by Eco1 acetyltransferase. Here, we explore how cohesin acetylation is linked to DNA replication. Biochemical reconstitution of replication-coupled cohesin acetylation reveals that transient DNA structures, which form during DNA replication, control the acetylation reaction. As polymerases complete lagging strand replication, strand displacement synthesis produces DNA flaps that are trimmed to result in nicked double-stranded DNA. Both flaps and nicks stimulate cohesin acetylation, while subsequent nick ligation to complete Okazaki fragment maturation terminates the acetylation reaction. A flapped or nicked DNA substrate constitutes a transient molecular clue that directs cohesin acetylation to a window behind the replication fork, next to where cohesin likely entraps both sister chromatids. Our results provide an explanation for how DNA replication is linked to sister chromatid cohesion establishment.
在 DNA 复制的同时，染色体黏合蛋白复合物在新复制的姐妹染色单体之间建立黏合。黏合的建立需要 Eco1 乙酰转移酶对保守的黏合蛋白赖氨酸残基进行乙酰化。在这里，我们探讨了黏合蛋白乙酰化如何与 DNA 复制相关联。复制偶联的黏合蛋白乙酰化的生化重建揭示，在 DNA 复制过程中形成的瞬时 DNA 结构控制着乙酰化反应。随着聚合酶完成滞后链复制，链位移合成产生 DNA 瓣片，这些瓣片被修剪，导致切口双链 DNA。瓣片和切口都能刺激黏合蛋白乙酰化，而随后的切口连接完成 Okazaki 片段成熟则终止乙酰化反应。一个有瓣片或有切口的 DNA 底物构成了一个短暂的分子线索，将黏合蛋白乙酰化引导到复制叉后面的一个窗口，就在黏合蛋白可能捕获两个姐妹染色单体的地方附近。我们的结果为 DNA 复制如何与姐妹染色单体黏合的建立联系提供了一个解释。
