综述: 组蛋白去乙酰化酶的结构及应用

组蛋白赖氨酸乙酰化是目前研究最为广泛和深入的组蛋白翻译后修饰之一,在染色质重塑和基因表达调控等方面发挥重要作用,这种修饰在体内受到组蛋白乙酰化酶和去乙酰化酶的高度动态调控．除了以组蛋白为底物外,组蛋白去乙酰化酶还可以催化多种非组蛋白的去乙酰化,参与多种生命过程的调节．本文围绕四类人源组蛋白去乙酰化酶,综述了其分类依据、结构与功能特点、催化反应的分子机制,以及针对这些组蛋白去乙酰化酶的抑制剂和激动剂的开发和应用等方面的研究进展．     

组蛋白脱乙酰化酶及其与基因转录的关系

含有组蛋白脱乙酰化酶活性的分子有两类：一类是与酵母RPD3同源的分子,另一类是与RPD3不同源的分子.它们各有其不同的来源,存在于各自的复合物中,催化不完全相同的组蛋白或其他蛋白质脱乙酰化;这些脱乙酰化酶与基因转录的调控存在着密切的关系, 主要是介导基因转录的抑制.     

Suppression of centrosome duplication and amplification by deacetylases

Centrosome duplication is controlled both negatively and positively by a number of proteins. The activities and stabilities of those regulatory proteins are in many cases controlled by posttranslational modifications. Although acetylation and deacetylation are highly common posttranslational modifications, their roles in the regulation of centrosome duplication had not been closely examined. Here, through focusing on the deacetylases, we investigated the role of acetylation/deacetylation in the regulation of centrosome duplication and induction of abnormal amplification of centrosomes. We found that the deacetylation event negatively controls centrosome duplication and amplification. Of the 18 total known deacetylases (HDAC1–11, SIRT1–7), ten deacetylases possess the activity to suppress centrosome amplification, and their centrosome amplification suppressing activities are strongly associated with their abilities to localize to centrosomes. Among them, HDAC1, HDAC5 and SIRT1 show the highest suppressing activities, but each of them suppresses centrosome duplication and/or amplification with its unique mechanism.     

Suppression of centrosome duplication and amplification by deacetylases

Centrosome duplication is controlled both negatively and positively by a number of proteins. The activities and stabilities of those regulatory proteins are in many cases controlled by posttranslational modifications. Although acetylation and deacetylation are highly common posttranslational modifications, their roles in the regulation of centrosome duplication had not been closely examined. Here, through focusing on the deacetylases, we investigated the role of acetylation/deacetylation in the regulation of centrosome duplication and induction of abnormal amplification of centrosomes. We found that the deacetylation event negatively controls centrosome duplication and amplification. Of the 18 total known deacetylases (HDAC1–11, SIRT1–7), ten deacetylases possess the activity to suppress centrosome amplification, and their centrosome amplification suppressing activities are strongly associated with their abilities to localize to centrosomes. Among them, HDAC1, HDAC5 and SIRT1 show the highest suppressing activities, but each of them suppresses centrosome duplication and/or amplification with its unique mechanism.     

酿酒酵母组蛋白乙酰化修饰及其对基因表达的调控

真核生物核小体组蛋白修饰引起染色质重塑(Chromatin remodeling)是表观遗传的重要调控机制.乙酰化修饰(Acetylation modification)是其中一种重要的方式.组蛋白乙酰化修饰位点集中在各种组蛋白N末端赖氨酸残基上.细胞内存在功能拮抗的多种乙酰基转移酶和去乙酰化酶,二者相互竞争,共同调节组蛋白的乙酰化状态,通过影响核小体结构的致密性,并在多种效应分子的参与下,实现对基因的表达调控.以真核模式生物酿酒酵母(Saccharomyces cerevisiae)为对象,综述乙酰基转移酶和去乙酰化酶的种类、作用特点以及其基因调控的分子机制等方面的最新研究进展.     

Selective repression of YKL-40 by NF-kappaB in glioma cell lines involves recruitment of histone deacetylase-1 and -2

Here we show that in contrast to other cancer types, tumor necrosis factor (TNF)-alpha suppresses YKL-40 expression in glioma cell lines in a nuclear factor kappaB (NF-kappaB) dependent manner. Even though TNF-alpha causes recruitment of p65 and p50 subunits of NF-kappaB to the YKL-40 promoter in all cell types, recruitment of histone deacetylases (HDAC)-1 and -2, and a consequent deacetylation of histone H3 at the YKL-40 promoter occurs only in glioma cells. Importantly, using chromatin immunoprecipitation assays in frozen glioblastoma multiforme tissues, we show that YKL-40 levels decrease consistent with HDAC1 recruitment despite high levels of nuclear p-p65. This study presents a paradigm for NF-kappaB regulation of one of its targets in a strict cell type specific manner.     

Current role of mammalian sirtuins in DNA repair

Cellular DNA is constantly challenged by damage-inducing factors derived from exogenous or endogenous sources. Thus, to protect against DNA damage, cells have evolved complex and finely regulated mechanisms collectively known as DNA-damage response (DDR). However, DNA repair in eukaryotes does not occur merely in naked DNA but also within a highly organized and compacted chromatin environment, which ultimately participates in regulating DDR pathways. Thus, remodelling of the chromatin surrounding areas containing damaged DNA is required to allow access to the DNA repair machinery, as well as post-translational modifications in many repair factors to recruit and activate them at the damaged site. Notably, proteins such as sirtuins, which are NAD+-dependent deacetylases, have evolved to modulate multiple repair pathways through deacetylation of some repair factors, influencing chromatin accessibility or indirectly modulating cell cycle and preventing oxidative stress. In this way, the purpose of this review is to summarize the recent knowledge that links sirtuins with DNA repair, with a particular emphasis on the molecular mechanisms associated with coordination and regulation of this vital process.     

The multi zinc-finger protein Trps1 acts as a regulator of histone deacetylation during mitosis

TRPS1, the gene mutated in human "Tricho-Rhino-Phalangeal syndrome," encodes a multi zinc-finger nuclear regulator of chondrocyte proliferation and differentiation. Here, we have identified a new function of Trps1 in controlling mitotic progression in chondrocytes. Loss of Trps1 in mice leads to an increased proportion of cells arrested in mitosis and, subsequently, to chromosome segregation defects. Searching for the molecular basis of the defect, we found that Trps1 acts as regulator of histone deacetylation. Trps1 interacts with two histone deacetylases, Hdac1 and Hdac4, thereby increasing their activity. Loss of Trps1 results in histone H3 hyperacetylation, which is maintained during mitosis. Consequently, chromatin condensation and binding of HP1 is impaired, and Trps1-deficient chondrocytes accumulate in prometaphase. Overexpression of Hdac4 rescues the mitotic defect of Trps1-deficient chondrocytes, identifying Trps1 as an important regulator of chromatin deacetylation during mitosis in chondrocytes. Our data provide the first evidence that the control of mitosis can be linked to the regulation of chondrocyte differentiation by epigenetic consequences of altered Hdac activity.