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染色体长度影响复制诱导的拓扑应力。

Chromosome length influences replication-induced topological stress.

机构信息

Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers väg 3, 171 77 Stockholm, Sweden.

出版信息

Nature. 2011 Mar 17;471(7338):392-6. doi: 10.1038/nature09791. Epub 2011 Mar 2.

Abstract

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. Positive supercoiling can also be diminished if the advancing fork rotates along the DNA helix, but then sister chromatid intertwinings form in its wake. 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. Furthermore, non-functional 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.

摘要

在染色体复制过程中,父代 DNA 分子在前进的复制叉前方区域过度缠绕,即正超螺旋化。为了允许叉前进,拓扑异构酶必须通过引入瞬时 DNA 断裂来消除这种超螺旋张力。如果前进的叉沿着 DNA 螺旋旋转,也可以减少正超螺旋化,但随后姐妹染色单体在其后面形成相互缠绕。尽管有这些见解,但线性真核染色体上如何处理复制诱导的超螺旋压力在很大程度上仍然未知。在这里,我们表明这种压力随着酿酒酵母染色体的长度增加而增加。这突出表明,超螺旋张力是在染色体尺度上处理的,而不仅仅是在当前观点预测的拓扑闭合染色体域内处理。我们发现,I 型拓扑异构酶的抑制导致更长但不是更短的染色体的复制后期延迟。这种表型也表现在表达突变体版本的黏合蛋白和凝聚蛋白相关 Smc5/6 复合物的细胞中。Smc5/6 复合物的染色体关联位点的频率响应于染色体延长、染色体环化或拓扑异构酶 2 的失活而增加,所有这些都有可能增加姐妹染色单体相互缠绕的数量。此外,非功能 Smc6 在没有拓扑异构酶 2 功能的情况下减少了一轮复制后相互缠绕的姐妹质粒的积累。我们的结果表明,染色体的长度影响酿酒酵母中超螺旋张力释放的需求,并允许我们提出一个模型,其中 Smc5/6 复合物通过隔离在复制机制后面形成的新生染色单体相互缠绕来促进叉旋转。

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