Fragile site instability in Saccharomyces cerevisiae causes loss of heterozygosity by mitotic crossovers and break-induced replication.
Fragile site instability in Saccharomyces cerevisiae causes loss of heterozygosity by mitotic crossovers and break-induced replication.
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DOI：
10.1371/journal.pgen.1003817
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Casper AM
中科院分区：
文献类型：
--
作者：
Rosen DM;Younkin EM;Miller SD;Casper AM
抑癌基因座杂合性缺失 (LOH) 是癌症发生和进展的主要原因。缺失和有丝分裂重组均可导致 LOH。某些被称为常见脆弱位点的染色体位点在复制应激下容易受到 DNA 损伤，并且复制应激在早期肿瘤细胞中普遍存在。有大量证据表明肿瘤中常见的脆弱位点刺激了缺失，但脆弱位点在刺激有丝分裂重组（导致 LOH）中的作用尚不清楚。在这里，我们使用酵母模型系统来研究脆弱位点不稳定性与导致 LOH 的有丝分裂重组之间的关系。天然存在的脆弱位点 FS2 存在于酵母 III 号染色体的右臂上，我们分析了该染色体上的 LOH。我们报告说，导致酵母 III 号染色体右臂上 LOH 的自发有丝分裂 BIR 事件的频率高于预期，并且低水平聚合酶 α 造成的复制应激使有丝分裂重组增加了 12 倍。利用两个 III 号染色体同源物之间的单核苷酸多态性，我们绘制了重组事件的位置，并确定 FS2 是复制应激条件下有丝分裂相互交叉和断裂诱导的复制事件的强热点。肿瘤抑制基因杂合性缺失 (LOH) 会导致癌症，在肿瘤细胞中某些称为常见脆弱位点的染色体区域中经常观察到导致 LOH 的缺失。如果使用同源染色体而不是姐妹染色单体作为修复模板，则 LOH 也可能是由有丝分裂重组修复 DNA 损伤引起的。脆弱位点不稳定性通过与同源染色体的有丝分裂重组导致 LOH 的程度尚不清楚。我们评估了酿酒酵母 III 号染色体上的有丝分裂重组，该染色体包含一个天然存在的脆弱位点，称为 FS2。我们报告酵母 III 号染色体具有高频率的涉及同源染色体的自发有丝分裂重组。在刺激脆弱位点不稳定的条件下，酵母 III 号染色体上有丝分裂重组产生的 LOH 增加了 12 倍，而 FS2 是启动这些事件的热点。这些结果表明，人类常见脆弱位点的不稳定性可能会驱动有丝分裂重组修复途径，从而导致 LOH 并促进肿瘤发生。
Loss of heterozygosity (LOH) at tumor suppressor loci is a major contributor to cancer initiation and progression. Both deletions and mitotic recombination can lead to LOH. Certain chromosomal loci known as common fragile sites are susceptible to DNA lesions under replication stress, and replication stress is prevalent in early stage tumor cells. There is extensive evidence for deletions stimulated by common fragile sites in tumors, but the role of fragile sites in stimulating mitotic recombination that causes LOH is unknown. Here, we have used the yeast model system to study the relationship between fragile site instability and mitotic recombination that results in LOH. A naturally occurring fragile site, FS2, exists on the right arm of yeast chromosome III, and we have analyzed LOH on this chromosome. We report that the frequency of spontaneous mitotic BIR events resulting in LOH on the right arm of yeast chromosome III is higher than expected, and that replication stress by low levels of polymerase alpha increases mitotic recombination 12-fold. Using single-nucleotide polymorphisms between the two chromosome III homologs, we mapped the locations of recombination events and determined that FS2 is a strong hotspot for both mitotic reciprocal crossovers and break-induced replication events under conditions of replication stress. Loss of heterozygosity (LOH) at tumor-suppressor genes contributes to cancer, and deletions resulting in LOH are frequently observed in tumor cells at certain chromosomal regions known as common fragile sites. LOH can also result from repair of DNA damage by mitotic recombination, if the homologous chromosome rather than the sister chromatid is used as a repair template. The extent to which fragile site instability causes LOH by mitotic recombination with the homologous chromosome is unknown. We evaluated mitotic recombination on the yeast Saccharomyces cerevisiae chromosome III, which contains a naturally-occurring fragile site known as FS2. We report that yeast chromosome III has a high frequency of spontaneous mitotic recombination that involves the homologous chromosome. Under conditions that stimulate instability at the fragile site, LOH resulting from mitotic recombination on yeast chromosome III is increased 12-fold, and FS2 is a hotspot for initiating these events. These results suggest that instability at human common fragile sites may drive mitotic recombination repair pathways that cause LOH and promote tumorogenesis.
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影响因子：
4.5
作者：
Chung WH;Zhu Z;Papusha A;Malkova A;Ira G
通讯作者：
Ira G
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda