Histone deacetylases in Trypanosoma brucei:: two are essential and another is required for normal cell cycle progression
Histone deacetylases in Trypanosoma brucei:: two are essential and another is required for normal cell cycle progression
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DOI：
10.1046/j.1365-2958.2002.03018.x
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发表时间：
2002-07-01
影响因子：
3.6
通讯作者：
Horn, D
中科院分区：
文献类型：
--
作者：
Ingram, AK;Horn, D
可逆的蛋白质乙酰化被确立为具有重要调控意义的修饰。特别是，组蛋白乙酰化调节真核生物中遗传信息的获取。例如，I类和II类组蛋白脱乙酰基酶是参与细胞周期进展和分化的辅阻遏物复合物的调节成分。在这里，我们研究了这些酶在布氏锥虫，单鞭毛寄生原生动物分支非常早的真核谱系的功能。四个T编码组蛋白脱乙酰基酶直向同源物的布鲁氏菌基因已被鉴定、克隆和表征。预测的脱乙酰酶DAC 1 -4分别约为43、61、75和64 kDa。它们与哺乳动物和酵母I类（DAC 1和DAC 2）和II类（DAC 3和DAC 4）组蛋白脱乙酰酶有着显著的相似性，除DAC 2外，所有组蛋白脱乙酰酶都具有预测脱乙酰酶活性所需的关键残基。在基因靶向实验中，DAC 1和DAC 3似乎是必需的，而DAC 2和DAC 4不是生存力所必需的。在两种突变细胞类型中，dac 4突变体显示细胞周期的G（2）/M期延迟。我们的研究结果提供了DAC 1和DAC 3作为潜在化疗靶点的遗传学验证，并证明T。布氏杆菌表达至少三种可能的具有不同功能的组蛋白脱乙酰酶。
Reversible protein acetylation is established as a modification of major regulatory significance. In particular, histone acetylation regulates access to genetic information in eukaryotes. For example, class I and class II histone deacetylases are regulatory components of corepressor complexes involved in cell cycle progression and differentiation. Here, we have investigated the function of such enzymes in Trypanosoma brucei, mono-flagellated parasitic protozoa that branched very early from the eukaryotic lineage. Four T. brucei genes encoding histone deacetylase orthologues have been identified, cloned and characterized. The predicted deacetylases, DAC1-4 are approximately 43, 61, 75 and 64 kDa respectively. They share significant similarity with mammalian and yeast class I (DAC1 and DAC2) and class II (DAC3 and DAC4) histone deacetylases, and all except DAC2 have the critical residues predicted to be required for deacetylase activity. In gene targeting experiments, DAC1 and DAC3 appear to be essential whereas DAC2 and DAC4 are not required for viability. Of the two mutant cell types, the dac4 mutant displays a delay in the G(2)/M phase of the cell cycle. Our results provide genetic validation of DAC1 and DAC3 as potential chemotherapy targets and demonstrate that T. brucei expresses at least three probable histone deacetylases with distinct function.