Replicative age induces mitotic recombination in the ribosomal RNA gene cluster of Saccharomyces cerevisiae.
Replicative age induces mitotic recombination in the ribosomal RNA gene cluster of Saccharomyces cerevisiae.
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DOI：
10.1371/journal.pgen.1002015
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发表时间：
2011-03
期刊：
影响因子：
4.5
通讯作者：
Gottschling DE
中科院分区：
文献类型：
--
作者：
Lindstrom DL;Leverich CK;Henderson KA;Gottschling DE
体细胞突变有助于年龄相关疾病的发展。在早期的工作中，我们发现，在高频率下，老化的酿酒酵母二倍体细胞产生没有线粒体DNA的子代，导致呼吸能力丧失和核基因组杂合性丢失（洛）增加。在这里，我们使用最近开发的母亲富集计划来询问保持产生有呼吸能力的子细胞的能力的衰老细胞是否也会经历增加的基因组不稳定性。我们发现，这一群体表现出独特的基因组不稳定性表型，主要影响重复的核糖体RNA基因阵列（rDNA阵列）。当二倍体细胞经过其中值复制寿命时，同源染色体上rDNA阵列之间的重组率逐渐增加，导致在染色体XII右臂上>300个连续开放阅读框处产生洛缺失的突变事件。我们表明，虽然这些重组事件依赖于复制叉块蛋白Fob1，这种表型的基础是Fob1独立的老化过程。此外，我们提供的证据表明，这一衰老过程并不是由调节年轻细胞中rDNA重组的机制驱动的，包括rDNA阵列内的凝聚力丧失或Sir2功能丧失。相反，我们认为与年龄相关的rDNA重组增加是对衰老细胞中产生的DNA复制应激增加的反应。年龄与许多疾病（如癌症）的发病之间存在着惊人的相关性，这表明衰老过程本身可能有助于疾病的发展。癌症是一种遗传性疾病，由一系列有害的体细胞突变的积累引起，导致不受控制的增殖。在人类中，已经确定正常的突变率不足以解释老龄人口中癌症发病率的急剧增加，这表明突变率的变化是癌症发展的必要组成部分。在这里，我们发现，在芽殖酵母酿酒酵母的老化过程中导致一个重复的DNA序列元件，核糖体rDNA阵列内的同源重组率增加。虽然这些突变事件主要是在这个单一的位点开始，但它们会传播到染色体的末端，从而影响数百个基因。这些结果表明，衰老过程本身可能有助于增加突变率，并可能导致年龄相关疾病的发生。
Somatic mutations contribute to the development of age-associated disease. In earlier work, we found that, at high frequency, aging Saccharomyces cerevisiae diploid cells produce daughters without mitochondrial DNA, leading to loss of respiration competence and increased loss of heterozygosity (LOH) in the nuclear genome. Here we used the recently developed Mother Enrichment Program to ask whether aging cells that maintain the ability to produce respiration-competent daughters also experience increased genomic instability. We discovered that this population exhibits a distinct genomic instability phenotype that primarily affects the repeated ribosomal RNA gene array (rDNA array). As diploid cells passed their median replicative life span, recombination rates between rDNA arrays on homologous chromosomes progressively increased, resulting in mutational events that generated LOH at >300 contiguous open reading frames on the right arm of chromosome XII. We show that, while these recombination events were dependent on the replication fork block protein Fob1, the aging process that underlies this phenotype is Fob1-independent. Furthermore, we provide evidence that this aging process is not driven by mechanisms that modulate rDNA recombination in young cells, including loss of cohesion within the rDNA array or loss of Sir2 function. Instead, we suggest that the age-associated increase in rDNA recombination is a response to increasing DNA replication stress generated in aging cells. There is a striking correlation between age and the onset of many diseases, such as cancer, suggesting that the aging process itself can contribute to their development. Cancer is a genetic disease caused by the accumulation of a series of deleterious somatic mutations leading to unchecked proliferation. In humans, it is well established that normal mutation rates are not sufficient to account for the sharp increase in cancer rates in aging populations, suggesting a change in mutation rate is a necessary component of cancer development. Here, we find that the aging process in the budding yeast Saccharomyces cerevisiae leads to an increased rate of homologous recombination within a repetitive DNA sequence element, the ribosomal rDNA array. While these mutational events are initiated primarily at this single locus, they are propagated to the end of the chromosome and thus affect hundreds of genes. These results suggest that the aging process itself could contribute to increasing mutation rates and perhaps to the onset of age-associated disease.
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影响因子：
11.2
作者：
Bacolod MD;Schemmann GS;Giardina SF;Paty P;Notterman DA;Barany F
通讯作者：
Barany F
影响因子：
4.7
作者：
Andersen, Claus Lindbjerg;Wiuf, Carsten;Orntoft, Torben Falck
通讯作者：
Orntoft, Torben Falck
影响因子：
14.9
作者：
Benguría, A;Hernández, P;Schvartzman, JB
通讯作者：
Schvartzman, JB
影响因子：
10.5
作者：
Huang, Julie;Brito, Ilana L.;Moazed, Danesh
通讯作者：
Moazed, Danesh
DOI：
10.1073/pnas.261574398
发表时间：
2001-12-18
影响因子：
11.1
作者：
Bedalov, A;Gatbonton, T;Simon, JA
通讯作者：
Simon, JA