Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance.
Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance.
复制标题
DOI：
10.1371/journal.pgen.1002136
复制
发表时间：
2011-06
期刊：
影响因子：
4.5
通讯作者：
Araki H
中科院分区：
文献类型：
--
作者：
Tanaka S;Araki H
基因组不稳定性是人类癌细胞的标志。为了防止基因组不稳定，染色体DNA在每个细胞分裂周期中忠实地复制，真核细胞具有复杂的调控机制来实现这一目标。在这里，我们表明，不合时宜的激活复制起点在G1期是遗传毒性和诱导基因组不稳定性的芽殖酵母酿酒酵母。我们的数据表明，细胞保存低水平的起始因子Sld 2，以防止不合时宜的启动在正常的细胞周期期间，除了控制磷酸化的Sld 2和Sld 3的细胞周期蛋白依赖性激酶。虽然不合时宜的激活的起源是抑制在多个层面上，我们表明，一个单一的途径的失调可能会导致基因组的不稳定性，如总染色体重排（GCR）。此外，多个途径的同时失调导致甚至更严重的表型。这些发现强调了具有多种抑制机制以防止染色体复制的不合时宜的启动以在真核生物中保持稳定的基因组维持数代的重要性。染色体DNA复制在真核生物中以两步反应发生。在第一个反应中，称为许可，复制解旋酶在细胞周期的G1期以无活性形式加载到复制起点上。在第二个反应中，称为起始，复制解旋酶被激活，并建立复制叉。由于这种两步机制，许可和启动必须发生在细胞周期的不同时间。这两步调控的失败将导致染色体DNA的异质再复制，基因组完整性将丧失。虽然以前的作品已经建立了多个监管途径调节许可，少得多的是知道如何不合时宜（过早）启动，防止在G1期。在本文中，我们表明，不合时宜的激活复制起点在G1期被抑制在多个层面上。值得注意的是，单一途径的失调可导致基因组不稳定性;多个途径的同时失调导致更严重的表型，如非整倍性。因此，这些发现不仅表明了具有多种抑制机制以防止染色体复制过早启动的重要性，而且还应该帮助我们了解人类癌细胞中的复制可能是如何失调的，其中基因组经常不稳定。
Genomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins during the G1 phase is genotoxic and induces genomic instability in the budding yeast Saccharomyces cerevisiae. Our data indicate that cells preserve a low level of the initiation factor Sld2 to prevent untimely initiation during the normal cell cycle in addition to controlling the phosphorylation of Sld2 and Sld3 by cyclin-dependent kinase. Although untimely activation of origin is inhibited on multiple levels, we show that deregulation of a single pathway can cause genomic instability, such as gross chromosome rearrangements (GCRs). Furthermore, simultaneous deregulation of multiple pathways causes an even more severe phenotype. These findings highlight the importance of having multiple inhibitory mechanisms to prevent the untimely initiation of chromosome replication to preserve stable genome maintenance over generations in eukaryotes. Chromosomal DNA replication occurs as a two-step reaction in eukaryotes. In the first reaction, called licensing, the replicative helicase is loaded onto replication origin in an inactive form during the G1 phase of the cell cycle. In the second reaction, called initiation, the replicative helicase is activated, and replication forks are established. Because of this two-step mechanism, licensing and initiation must occur at different times in the cell cycle. Failure of this two-step regulation will cause heterogeneous re-replication of chromosomal DNA, and genome integrity will be lost. Although previous works have established that multiple regulatory pathways regulate licensing, much less is known about how untimely (premature) initiation is prevented during the G1 phase. In this paper, we show that untimely activation of replication origins during the G1 phase is inhibited on multiple levels. Notably, deregulation of a single pathway can cause genomic instability; simultaneous deregulation of multiple pathways causes a more severe phenotype, such as aneuploidy. Therefore, these findings not only indicate the importance of having multiple inhibitory mechanisms to prevent untimely initiation of chromosome replication but also should help us understand how replication might be deregulated in human cancer cells, in which the genome is frequently destabilized.
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DOI：
10.1073/pnas.92.25.11791
发表时间：
1995-12-05
影响因子：
11.1
作者：
ARAKI, H;LEEM, SH;SUGINO, A
通讯作者：
SUGINO, A
影响因子：
3.3
作者：
Green, BM;Li, JJ
通讯作者：
Li, JJ
DNA复制控制的丧失是基因扩增的有效诱导剂。
DOI：
10.1126/science.1190966
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Green BM;Finn KJ;Li JJ
通讯作者：
Li JJ
影响因子：
78.5
作者：
Blow, J. Julian;Gillespie, Peter J.
通讯作者：
Gillespie, Peter J.
影响因子：
64.5
作者：
Kumagai A;Shevchenko A;Shevchenko A;Dunphy WG
通讯作者：
Dunphy WG