A novel role for Dun1 in the regulation of origin firing upon hyper-acetylation of H3K56.
A novel role for Dun1 in the regulation of origin firing upon hyper-acetylation of H3K56.
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Dun1在H3K56的超乙酰化过程中调控起始激发的新作用。
DOI：
10.1371/journal.pgen.1009391
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发表时间：
2021-03
期刊：
影响因子：
4.5
通讯作者：
Kupiec M
中科院分区：
文献类型：
--
作者：
Gershon L;Kupiec M
在DNA复制过程中，新合成的组蛋白被掺入复制姐妹染色单体的染色质中。在酿酒酵母中，新的组蛋白H3分子在赖氨酸56处被乙酰化。这种修饰在细胞周期中受到仔细的调节，任何对这一过程的破坏都是基因组不稳定性的来源。在这里，我们表明，蛋白激酶Dun1是必要的，以保持活力，在组蛋白脱乙酰酶Hst 3和Hst 4，去除乙酰基部分从组蛋白H3的情况下。这种致死性不是由于Dun1在上调dNTP中的良好表征的作用，而是因为需要Dun1来抵消抑制晚期放电起源的活性的检查点激酶Rad53（人CHK2）。删除CTF18（编码替代RFC样复合物（RLC）的大亚基，但不删除Elg1或Rad24 RLC的组分）足以克服具有超乙酰化组蛋白的细胞对Dun1的依赖性。我们发现Ctf18的有害功能取决于它与前导链聚合酶Pol ε的相互作用。因此，我们的研究结果表明，具有超乙酰化组蛋白的细胞的主要问题是其时间和复制程序的调节，并揭示了Dun1蛋白激酶和Ctf18夹钳装载器的新功能。在细胞核内，DNA包裹在一种叫做组蛋白的蛋白质周围。在DNA复制时，新合成的H3组蛋白在赖氨酸56处被乙酰化。这种乙酰化对细胞是重要的，因为当它不被及时去除时，它会导致基因组不稳定。我们已经研究了这种不稳定性的来源，并发现通常与dNTP（DNA的构建模块）的调节有关的激酶Dun1在组蛋白过度乙酰化时具有新的、不依赖于dNTP的重要作用。Dun1的重要作用是调节DNA复制的时间程序。因此，我们的研究结果揭示了细胞中无法调节组蛋白乙酰化的主要缺陷，同时揭示了具有基因组稳定性维持作用的良好特征的蛋白质的新功能。
During DNA replication newly synthesized histones are incorporated into the chromatin of the replicating sister chromatids. In the yeast Saccharomyces cerevisiae new histone H3 molecules are acetylated at lysine 56. This modification is carefully regulated during the cell cycle, and any disruption of this process is a source of genomic instability. Here we show that the protein kinase Dun1 is necessary in order to maintain viability in the absence of the histone deacetylases Hst3 and Hst4, which remove the acetyl moiety from histone H3. This lethality is not due to the well-characterized role of Dun1 in upregulating dNTPs, but rather because Dun1 is needed in order to counteract the checkpoint kinase Rad53 (human CHK2) that represses the activity of late firing origins. Deletion of CTF18, encoding the large subunit of an alternative RFC-like complex (RLC), but not of components of the Elg1 or Rad24 RLCs, is enough to overcome the dependency of cells with hyper-acetylated histones on Dun1. We show that the detrimental function of Ctf18 depends on its interaction with the leading strand polymerase, Polε. Our results thus show that the main problem of cells with hyper-acetylated histones is the regulation of their temporal and replication programs, and uncover novel functions for the Dun1 protein kinase and the Ctf18 clamp loader. Within the cell’s nucleus the DNA is wrapped around proteins called histones. Upon DNA replication, newly synthesized H3 histones are acetylated at lysine 56. This acetylation is significant for the cell because when it is not removed in a timely manner it leads to genomic instability. We have investigated the source of this instability and discovered that the kinase Dun1, usually implicated in the regulation of dNTPs, the building blocks of DNA, has a novel, dNTP-independent, essential role when histones are hyper-acetylated. The essential role of Dun1 is in the regulation of the temporal program of DNA replication. Thus, our results uncover what the main defect is in cells unable to regulate the acetylation of histones, while revealing new functions for well-characterized proteins with roles in genome stability maintenance.
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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
DOI：
10.1074/jbc.ra118.005439
发表时间：
2018-11-23
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Graham WJ 5th;Putnam CD;Kolodner RD
通讯作者：
Kolodner RD
影响因子：
10.5
作者：
BRACHMANN, CB;SHERMAN, JM;BOEKE, JD
通讯作者：
BOEKE, JD
影响因子：
5.3
作者：
Fillingham, Jeffrey;Recht, Judith;Greenblatt, Jack F.
通讯作者：
Greenblatt, Jack F.
影响因子：
4.5
作者：
Alvaro D;Lisby M;Rothstein R
通讯作者：
Rothstein R