Chromosome length influences replication-induced topological stress
Chromosome length influences replication-induced topological stress
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DOI：
10.1038/nature09791
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发表时间：
2011-03-17
期刊：
影响因子：
64.8
通讯作者：
Sjogren, Camilla
中科院分区：
文献类型：
--
作者：
Kegel, Andreas;Betts-Lindroos, Hanna;Sjogren, Camilla
在染色体复制过程中，亲本DNA分子在前进的复制叉之前的区域变得过度缠绕，或正超螺旋。为了允许分叉进展，这种超螺旋张力必须通过拓扑异构酶来消除，拓扑异构酶通过引入瞬时DNA断裂来运作（1）。如果前进叉沿着DNA螺旋旋转，正超螺旋也会减少，但随后姐妹染色单体缠绕形成（1，2）。尽管有这些见解，它仍然在很大程度上是未知的复制诱导的超螺旋应力是如何处理的线性，真核染色体。在这里，我们表明，这种压力增加与酿酒酵母染色体的长度。这突出了超螺旋张力是在染色体尺度上处理的可能性，而不仅仅是像目前的观点预测的那样在拓扑学上封闭的染色体结构域中处理。我们发现，I型拓扑异构酶的抑制导致较长的，但不是较短的，染色体的后期复制延迟。这种表型也显示细胞表达的突变形式的凝聚素和凝聚素相关的Smc 5/6复合物。Smc 5/6复合体的染色体联合位点的频率随着染色体延长、染色体环化或拓扑异构酶2失活而增加，所有这些都有可能增加姐妹染色单体缠绕的数量（3）。此外，在拓扑异构酶2功能不存在的情况下，非功能性Smc 6在一轮复制后减少了交织的姐妹质粒的积累。我们的研究结果表明，染色体的长度影响需要的超螺旋张力释放酿酒酵母，并允许我们提出一个模型，其中Smc 5/6复合物有利于叉旋转隔离新生的染色单体缠绕，形成背后的复制机器。
During chromosome duplication the parental DNA molecule becomes overwound, or positively supercoiled, in the region ahead of the advancing replication fork. To allow fork progression, this superhelical tension has to be removed by topoisomerases, which operate by introducing transient DNA breaks(1). Positive supercoiling can also be diminished if the advancing fork rotates along the DNA helix, but then sister chromatid intertwinings form in its wake(1,2). Despite these insights it remains largely unknown how replication-induced superhelical stress is dealt with on linear, eukaryotic chromosomes. Here we show that this stress increases with the length of Saccharomyces cerevisiae chromosomes. This highlights the possibility that superhelical tension is handled on a chromosome scale and not only within topologically closed chromosomal domains as the current view predicts. We found that inhibition of type I topoisomerases leads to a late replication delay of longer, but not shorter, chromosomes. This phenotype is also displayed by cells expressing mutated versions of the cohesin-and condensin-related Smc5/6 complex. The frequency of chromosomal association sites of the Smc5/6 complex increases in response to chromosome lengthening, chromosome circularization, or inactivation of topoisomerase 2, all having the potential to increase the number of sister chromatid intertwinings(3). Furthermore, nonfunctional Smc6 reduces the accumulation of intertwined sister plasmids after one round of replication in the absence of topoisomerase 2 function. Our results demonstrate that the length of a chromosome influences the need of superhelical tension release in Saccharomyces cerevisiae, and allow us to propose a model where the Smc5/6 complex facilitates fork rotation by sequestering nascent chromatid intertwinings that form behind the replication machinery.