Rtt109 prevents hyper-amplification of ribosomal RNA genes through histone modification in budding yeast.
Rtt109 prevents hyper-amplification of ribosomal RNA genes through histone modification in budding yeast.
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DOI：
10.1371/journal.pgen.1003410
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发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Kobayashi T
中科院分区：
文献类型：
--
作者：
Ide S;Saka K;Kobayashi T
编码核糖体RNA的基因是真核生物基因组中最丰富的。它们存在于串联重复的簇中，在某些情况下总共有数百个拷贝。由于其重复结构，核糖体RNA基因（rDNA）很容易在重复簇内的重组事件中丢失。我们以前确定了一个独特的基因扩增系统驱动的不平等姐妹染色单体重组DNA复制过程中。该系统补偿这种拷贝数损失，从而保持适当的拷贝数。在这里，通过对调节rDNA拷贝数的基因进行全基因组筛选，我们发现rtt 109突变体表现出超扩增表型（比野生型水平高103倍）。RTT 109编码乙酰转移酶，乙酰化组蛋白H3的赖氨酸56，并在复制偶联核小体组装中发挥作用。相对于不相等的姐妹染色单体重组为基础的扩增（101个拷贝/细胞分裂），rtt 109突变体中的超扩增率非常高（>100个拷贝/细胞分裂）。在该突变体中未观察到促进不等姐妹染色单体重组的粘着蛋白解离。在超扩增期间，通过rDNA中的染色体内重组产生的染色体外rDNA环（ERC）的水平降低。有趣的是，在扩增过程中，含有rDNA单元的质粒作为串联阵列整合到rDNA中。这些结果支持的想法，串联DNA阵列的生产和纳入通过滚环型复制。我们认为，在rtt 109突变体中，rDNA过度扩增是由不受控制的滚环型复制引起的。基因扩增是细胞增加基因产物丰度的主要策略之一。我们一直在研究酵母中核糖体RNA基因簇（也称为rDNA（核糖体DNA））的扩增，发现在重复序列之间意外的有害重组事件后，不等姐妹染色单体重组增加了拷贝数。这种扩增是高度调节的，当拷贝数达到150时停止。我们分离的突变体，包括rtt 109，它具有异常高的rDNA拷贝数。RTT 109编码影响染色质结构的乙酰转移酶。在突变体中，在两栖动物的早期发育阶段观察到的滚环型扩增，卵子发生。我们推测RTT 109在调节rDNA扩增模式中起关键作用。基因拷贝数（扩增）的变化已在多种生物体中广泛观察到，有助于有益的适应和病理学（例如，癌症）。我们的研究结果揭示了基因扩增的分子机制。
The genes encoding ribosomal RNA are the most abundant in the eukaryotic genome. They reside in tandem repetitive clusters, in some cases totaling hundreds of copies. Due to their repetitive structure, ribosomal RNA genes (rDNA) are easily lost by recombination events within the repeated cluster. We previously identified a unique gene amplification system driven by unequal sister-chromatid recombination during DNA replication. The system compensates for such copy number losses, thus maintaining proper copy number. Here, through a genome-wide screen for genes regulating rDNA copy number, we found that the rtt109 mutant exhibited a hyper-amplification phenotype (∼3 times greater than the wild-type level). RTT109 encodes an acetyl transferase that acetylates lysine 56 of histone H3 and which functions in replication-coupled nucleosome assembly. Relative to unequal sister-chromatid recombination-based amplification (∼1 copy/cell division), the rate of the hyper-amplification in the rtt109 mutant was extremely high (>100 copies/cell division). Cohesin dissociation that promotes unequal sister-chromatid recombination was not observed in this mutant. During hyper-amplification, production level of extra-chromosomal rDNA circles (ERC) by intra-chromosomal recombination in the rDNA was reduced. Interestingly, during amplification, a plasmid containing an rDNA unit integrated into the rDNA as a tandem array. These results support the idea that tandem DNA arrays are produced and incorporated through rolling-circle-type replication. We propose that, in the rtt109 mutant, rDNA hyper-amplification is caused by uncontrolled rolling-circle-type replication. Gene amplification is one of the major strategies used by cells to increase the abundance of gene products. We have been studying amplification of the ribosomal RNA genes cluster, also known as rDNA (ribosomal DNA), in yeast and found that unequal sister-chromatid recombination increased copy number following accidental deleterious recombination events among the repeats. This amplification is highly regulated and ceases when the copy number reaches ∼150. We isolated mutants, including rtt109, which have abnormally high copy numbers of rDNA. RTT109 encodes an acetyl transferase that affects chromatin structure. In the mutant, rolling circle-type amplification that is observed in the early developmental stage in amphibians, oogenesis occured. We speculate that RTT109 plays a key role in regulating the mode of rDNA amplification. Variation in gene copy number (amplification) has been widely observed in a variety of organisms, contributing to both beneficial adaptation and pathology (e.g., cancer). Our results shed new light on molecular mechanisms of gene amplification.
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DOI：
10.1126/science.1135862
发表时间：
2007-02-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Driscoll R;Hudson A;Jackson SP
通讯作者：
Jackson SP
影响因子：
56.9
作者：
BROWN, DD;DAWID, IB
通讯作者：
DAWID, IB
影响因子：
3.8
作者：
Duro, Eris;Vaisica, Jessica A.;Rouse, John
通讯作者：
Rouse, John
DOI：
10.1101/sqb.2000.65.297
发表时间：
2000-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
Imai, S;Johnson, FB;Guarente, L
通讯作者：
Guarente, L
影响因子：
5.3
作者：
Fillingham, Jeffrey;Recht, Judith;Greenblatt, Jack F.
通讯作者：
Greenblatt, Jack F.