FACT prevents the accumulation of free histones evicted from transcribed chromatin and a subsequent cell cycle delay in G1.
FACT prevents the accumulation of free histones evicted from transcribed chromatin and a subsequent cell cycle delay in G1.
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DOI：
10.1371/journal.pgen.1000964
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发表时间：
2010-05-20
期刊：
影响因子：
4.5
通讯作者：
Chávez S
中科院分区：
文献类型：
--
作者：
Morillo-Huesca M;Maya D;Muñoz-Centeno MC;Singh RK;Oreal V;Reddy GU;Liang D;Géli V;Gunjan A;Chávez S
FACT复合体参与转录延伸过程中染色质的组装和拆解。酵母突变型SPT16基因编码一个FACT亚基，它改变了G1期细胞周期蛋白的表达，并在G1/S转换过程中出现缺陷。在这里，我们证明了染色质重组因子的功能障碍，如FACT或Spt6，通过特异性地触发对其启动子的抑制，下调了编码周期蛋白的基因的表达，该基因调节START中的G1长度(CLN3)。Spt16突变体经历的G1延迟不是由DNA损伤检查点介导的，尽管RAD53突变(否则与组蛋白降解有关)增强了spt16-197的细胞周期缺陷。我们揭示了事实功能障碍如何触发从转录的染色质中驱逐的游离组蛋白的积累。这种累积在rad53背景中被增强，并导致G1中的延迟。我们一贯地表明，野生型细胞中组蛋白的过度表达下调了START中CLN3的表达，并导致G1期的延迟。我们的工作表明，染色质重组因子是控制可能从转录的染色质中释放的游离组蛋白的关键因素，并描述了一种新的细胞周期现象，即允许细胞在开始DNA复制之前对过量的组蛋白做出反应。长长的基因组DNA被包装在一种名为染色质的高度组织化的核蛋白结构中，其基本亚单位是核小体，核小体是由DNA包裹在称为组蛋白的八聚体蛋白质周围形成的。核小体需要被分解，才能通过RNA聚合酶进行DNA转录。在DNA转录过程中，拆卸/重组过程的一个重要因素是事实的复杂性。我们研究了酵母FACT突变体的一种表型，即在开始DNA复制之前细胞周期分裂过程中特定步骤的延迟。事实突变导致的功能障碍会导致CLN3基因的下调，该基因控制着细胞周期中特定步骤的长度。事实上，功能障碍还会增加转录过程中染色质释放的游离组蛋白水平，Spt16突变体的表型会因第二个突变而增强，该突变影响一种调节DNA修复和过量组蛋白降解的蛋白质。此外，我们发现，在野生型细胞中，组蛋白的过度表达会导致DNA复制之前的细胞周期延迟。我们的结果指出了染色质动力学和细胞周期调控之间的一种迄今未知的联系。
The FACT complex participates in chromatin assembly and disassembly during transcription elongation. The yeast mutants affected in the SPT16 gene, which encodes one of the FACT subunits, alter the expression of G1 cyclins and exhibit defects in the G1/S transition. Here we show that the dysfunction of chromatin reassembly factors, like FACT or Spt6, down-regulates the expression of the gene encoding the cyclin that modulates the G1 length (CLN3) in START by specifically triggering the repression of its promoter. The G1 delay undergone by spt16 mutants is not mediated by the DNA–damage checkpoint, although the mutation of RAD53, which is otherwise involved in histone degradation, enhances the cell-cycle defects of spt16-197. We reveal how FACT dysfunction triggers an accumulation of free histones evicted from transcribed chromatin. This accumulation is enhanced in a rad53 background and leads to a delay in G1. Consistently, we show that the overexpression of histones in wild-type cells down-regulates CLN3 in START and causes a delay in G1. Our work shows that chromatin reassembly factors are essential players in controlling the free histones potentially released from transcribed chromatin and describes a new cell cycle phenomenon that allows cells to respond to excess histones before starting DNA replication. Lengthy genomic DNA is packed in a highly organized nucleoprotein structure called chromatin, whose basic subunit is the nucleosome which is formed by DNA wrapped around an octamer of proteins called histones. Nucleosomes need to be disassembled to allow DNA transcription by RNA polymerases. An essential factor for the disassembly/reassembly process during DNA transcription is the FACT complex. We investigated a phenotype of yeast FACT mutants, a delay in a specific step of the cell cycle division process immediately prior to starting DNA replication. The dysfunction caused by the FACT mutation causes a downregulation of a gene, CLN3, which controls the length of that specific step of the cell cycle. FACT dysfunction also increases the level of the free histones released from chromatin during transcription, and the phenotype of the Spt16 mutant is enhanced by a second mutation affecting a protein that regulates DNA repair and excess histone degradation. Moreover, we show that the overexpression of histones causes a cell cycle delay before DNA replication in wild-type cells. Our results point out a so-far unknown connection between chromatin dynamics and the regulation of the cell cycle.
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