Genome Damage and Stability Centre, School of Life Sciences, Science Park Road, University of Sussex, Falmer, Brighton, East Sussex BN1 9RQ, UK.
Genome Damage and Stability Centre, School of Life Sciences, Science Park Road, University of Sussex, Falmer, Brighton, East Sussex BN1 9RQ, UK.
Mol Cell. 2020 May 21;78(4):739-751.e8. doi: 10.1016/j.molcel.2020.03.013. Epub 2020 Apr 6.
DNA topological stress inhibits DNA replication fork (RF) progression and contributes to DNA replication stress. In Saccharomyces cerevisiae, we demonstrate that centromeric DNA and the rDNA array are especially vulnerable to DNA topological stress during replication. The activity of the SMC complexes cohesin and condensin are linked to both the generation and repair of DNA topological-stress-linked damage in these regions. At cohesin-enriched centromeres, cohesin activity causes the accumulation of DNA damage, RF rotation, and pre-catenation, confirming that cohesin-dependent DNA topological stress impacts on normal replication progression. In contrast, at the rDNA, cohesin and condensin activity inhibit the repair of damage caused by DNA topological stress. We propose that, as well as generally acting to ensure faithful genetic inheritance, SMCs can disrupt genome stability by trapping DNA topological stress.
DNA 拓扑结构压力会抑制 DNA 复制叉（RF）的前进，并导致 DNA 复制压力。在酿酒酵母中，我们证明了在复制过程中，着丝粒 DNA 和 rDNA 序列特别容易受到 DNA 拓扑结构压力的影响。SMC 复合物黏合蛋白和凝聚素的活性与这些区域中 DNA 拓扑结构相关损伤的产生和修复都有关联。在黏合蛋白富集的着丝粒处，黏合蛋白的活性会导致 DNA 损伤的积累、RF 旋转和预链化，这证实了黏合蛋白依赖性 DNA 拓扑结构压力会对正常复制进程产生影响。相比之下，在 rDNA 处，黏合蛋白和凝聚素的活性会抑制 DNA 拓扑结构压力引起的损伤修复。我们提出，SMC 除了通常作用于确保遗传物质的忠实传递之外，还可以通过捕获 DNA 拓扑结构压力来破坏基因组稳定性。
