Grozinger C M, Hassig C A, Schreiber S L
Departments of Chemistry and Chemical Biology and Molecular and Cellular Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4868-73. doi: 10.1073/pnas.96.9.4868.
Gene expression is in part controlled by chromatin remodeling factors and the acetylation state of nucleosomal histones. The latter process is regulated by histone acetyltransferases and histone deacetylases (HDACs). Previously, three human and five yeast HDAC enzymes had been identified. These can be categorized into two classes: the first class represented by yeast Rpd3-like proteins and the second by yeast Hda1-like proteins. Human HDAC1, HDAC2, and HDAC3 proteins are members of the first class, whereas no class II human HDAC proteins had been identified. The amino acid sequence of Hda1p was used to search the GenBank/expressed sequence tag databases to identify partial sequences from three putative class II human HDAC proteins. The corresponding full-length cDNAs were cloned and defined as HDAC4, HDAC5, and HDAC6. These proteins possess certain features present in the conserved catalytic domains of class I human HDACs, but also contain additional sequence domains. Interestingly, HDAC6 contains an internal duplication of two catalytic domains, which appear to function independently of each other. These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A. Coimmunoprecipitation experiments indicate that these HDAC proteins are not components of the previously identified HDAC1 and HDAC2 NRD and mSin3A complexes. However, HDAC4 and HDAC5 associate with HDAC3 in vivo. This finding suggests that the human class II HDAC enzymes may function in cellular processes distinct from those of HDAC1 and HDAC2.
基因表达部分受染色质重塑因子和核小体组蛋白的乙酰化状态控制。后一过程由组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDACs）调节。此前，已鉴定出三种人类和五种酵母HDAC酶。这些酶可分为两类：第一类以酵母Rpd3样蛋白为代表，第二类以酵母Hda1样蛋白为代表。人类HDAC1、HDAC2和HDAC3蛋白属于第一类，而尚未鉴定出II类人类HDAC蛋白。利用Hda1p的氨基酸序列搜索GenBank/表达序列标签数据库，以鉴定三种假定的II类人类HDAC蛋白的部分序列。克隆了相应的全长cDNA，并将其定义为HDAC4、HDAC5和HDAC6。这些蛋白具有I类人类HDAC保守催化结构域中的某些特征，但也包含额外的序列结构域。有趣的是，HDAC6包含两个催化结构域的内部重复，这两个结构域似乎相互独立发挥作用。这些II类HDAC蛋白在人类组织中具有不同的mRNA表达，并具有体外HDAC活性，该活性可被曲古抑菌素A抑制。免疫共沉淀实验表明，这些HDAC蛋白不是先前鉴定的HDAC1和HDAC2 NRD及mSin3A复合物的组成成分。然而，HDAC4和HDAC5在体内与HDAC3相关联。这一发现表明，人类II类HDAC酶可能在与HDAC1和HDAC2不同的细胞过程中发挥作用。
