Molecular evolution of the histone deacetylase family: Functional implications of phylogenetic analysis
Molecular evolution of the histone deacetylase family: Functional implications of phylogenetic analysis
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DOI：
10.1016/j.jmb.2004.02.006
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发表时间：
2004-04-16
影响因子：
5.6
通讯作者：
Goodson, HV
中科院分区：
文献类型：
--
作者：
Gregoretti, IV;Lee, YM;Goodson, HV
组蛋白去乙酰化酶（HDACs）修饰核心组蛋白，并参与既能抑制又能增强转录的大型调控复合物。近期研究表明，一些HDACs也能作用于非组蛋白。由于HDAC抑制剂似乎是治疗癌症及多种其他疾病的有前景的药物，人们对这些酶的兴趣日益增加。到目前为止，在人类中已鉴定出11种HDAC家族成员，但很少有被详细描述的。为了更好地确定这些蛋白质的生物学功能，充分利用在其他系统中进行的研究，并协助药物研发工作，我们对所有已完全测序的自由生活生物中的所有HDAC相关蛋白质进行了系统发育分析。先前的分析将非沉默调节蛋白（sirtuin）HDACs分为两组，即1类和2类。我们发现HDACs可分为三个同样不同的组：1类、2类以及由与近期鉴定出的人类HDAC11基因相关的蛋白质组成的第三类。我们将这个新组称为“4类”，以将其与无关的“3类”沉默调节蛋白去乙酰化酶区分开来。对基因复制事件的分析表明，后生动物的共同祖先包含两个1类、两个2类和一个4类HDAC。根据这些进化关系对HDAC特性的研究可进行功能预测，其中包括HDAC蛋白质之间常见的自缔合。所有三类HDAC（包括4类）都存在于真细菌中。对细菌HDAC相关蛋白的系统发育分析表明，所有三类HDAC都早于组蛋白的进化，并提出了一些“组蛋白去乙酰化酶”的主要活性是针对非组蛋白底物的可能性。（C）2004年由爱思唯尔有限公司出版
Histone deacetylases (HDACs) modify core histones and participate in large regulatory complexes that both suppress and enhance transcription. Recent studies indicate that some HDACs can act on non-histone proteins as well. Interest in these enzymes is growing because HDAC inhibitors appear to be promising therapeutic agents against cancer and a variety of other diseases. Thus far, 11 members of the HDAC family have been identified in humans, but few have been characterized in detail. To better define the biological function of these proteins, make maximal use of studies performed in other systems, and assist in drug development efforts, we have performed a phylogenetic analysis of all HDAC-related proteins in all fully sequenced free-living organisms. Previous analyses have divided non-sirtuin HDACs into two groups, classes 1 and 2. We find that HDACs can be divided into three equally distinct groups: class 1, class 2, and a third class consisting of proteins related to the recently identified human HDAC11 gene. We term this novel group "class 4" to distinguish it from the unrelated "class 3" sirtuin deacetylases. Analysis of gene duplication events indicates that the common ancestor of metazoan organisms contained two class 1, two class 2, and a single class 4 HDAC. Examination of HDAC characteristics in light of these evolutionary relationships leads to functional predictions, among them that self-association is common among HDAC proteins. All three HDAC classes (including class 4) exist in eubacteria. Phylogenetic analysis of bacterial HDAC relatives suggests that all three HDAC classes precede the evolution of histone proteins and raises the possibility that the primary activity of some "histone deacetylase" enzymes is directed against nonhistone substrates. (C) 2004 Published by Elsevier Ltd.