Haldar Devyani, Kamakaka Rohinton T
Unit on Chromatin and Transcription, NICHD/NIH, 18 Library Dr., Bethesda, Maryland 20892, USA.
Eukaryot Cell. 2008 May;7(5):800-13. doi: 10.1128/EC.00379-07. Epub 2008 Mar 14.
The packaging of eukaryotic DNA into chromatin is likely to be crucial for the maintenance of genomic integrity. Histone acetylation and deacetylation, which alter chromatin accessibility, have been implicated in DNA damage tolerance. Here we show that Schizosaccharomyces pombe Hst4, a homolog of histone deacetylase Sir2, participates in S-phase-specific DNA damage tolerance. Hst4 was essential for the survival of cells exposed to the genotoxic agent methyl methanesulfonate (MMS) as well as for cells lacking components of the DNA damage checkpoint pathway. It was required for the deacetylation of histone H3 core domain residue lysine 56, since a strain with a point mutation of its catalytic domain was unable to deacetylate this residue in vivo. Hst4 regulated the acetylation of H3 K56 and was itself cell cycle regulated. We also show that MMS treatment resulted in increased acetylation of histone H3 lysine 56 in wild-type cells and hst4Delta mutants had constitutively elevated levels of histone H3 K56 acetylation. Interestingly, the level of expression of Hst4 decreased upon MMS treatment, suggesting that the cell regulates access to the site of DNA damage by changing the level of this protein. Furthermore, we find that the phenotypes of both K56Q and K56R mutants of histone H3 were similar to those of hst4Delta mutants, suggesting that proper regulation of histone acetylation is important for DNA integrity. We propose that Hst4 is a deacetylase involved in the restoration of chromatin structure following the S phase of cell cycle and DNA damage response.
真核生物DNA包装成染色质对于维持基因组完整性可能至关重要。组蛋白乙酰化和去乙酰化可改变染色质的可及性，与DNA损伤耐受有关。在此我们表明，粟酒裂殖酵母Hst4（组蛋白去乙酰化酶Sir2的同源物）参与S期特异性DNA损伤耐受。Hst4对于暴露于遗传毒性剂甲磺酸甲酯（MMS）的细胞以及缺乏DNA损伤检查点途径组分的细胞的存活至关重要。它是组蛋白H3核心结构域残基赖氨酸56去乙酰化所必需的，因为其催化结构域发生点突变的菌株在体内无法使该残基去乙酰化。Hst4调节H3 K56的乙酰化，其自身也受细胞周期调控。我们还表明，MMS处理导致野生型细胞中组蛋白H3赖氨酸56的乙酰化增加，而hst4Δ突变体中组蛋白H3 K56的乙酰化水平持续升高。有趣的是，MMS处理后Hst4的表达水平下降，这表明细胞通过改变该蛋白的水平来调节对DNA损伤位点的作用。此外，我们发现组蛋白H3的K56Q和K56R突变体的表型与hst4Δ突变体相似，这表明组蛋白乙酰化的适当调节对于DNA完整性很重要。我们提出，Hst4是一种去乙酰化酶，参与细胞周期S期和DNA损伤反应后染色质结构的恢复。
