DesJarlais Renee, Tummino Peter J
Lead Discovery, Janssen Research & Development , Spring House, Pennsylvania 19477, United States.
Biochemistry. 2016 Mar 22;55(11):1584-99. doi: 10.1021/acs.biochem.5b01210. Epub 2016 Jan 26.
In 1964, Alfrey and colleagues proposed that acetylation and methylation of histones may regulate RNA synthesis and described "the possibility that relatively minor modifications of histone structure, taking place on the intact protein molecule, offer a means of switching-on or off RNA synthesis at different loci along the chromosome" [Allfrey, V., Faulkner, R., and Mirsky, A. (1964) Proc. Natl. Acad. Sci. U.S.A. 51, 786]. Fifty years later, this prescient description provides a simple but conceptually accurate model for the biological role of histone post-translational modifications (PTMs). The basic unit of chromosomes is the nucleosome, with double-stranded DNA wrapped around a histone protein oligomer. The "tails" of histone proteins are post-translationally modified, which alters the physical properties of nucleosomes in a manner that impacts gene accessibility for transcription and replication. Enzymes that catalyze the addition and removal of histone PTMs, histone-modifying enzymes (HMEs), are present in large protein complexes, with DNA-binding proteins, ATP-dependent chromatin remodeling enzymes, and epigenetic reader proteins that bind to post-translationally modified histone residues [Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., and Schapira, M. (2012) Nat. Rev. Drug Discovery 11, 384-400]. The activity of HME complexes is coordinated with that of other chromatin-associated complexes that, together, regulate gene transcription, DNA repair, and DNA replication. In this context, the enzymes that catalyze addition and removal of histone PTMs are an essential component of the highly regulated mechanism for accessing compacted DNA. To fully understand the function of HMEs, the structure of nucleosomes, their natural substrate, will be described. Each major class of HMEs subsequently will be discussed with regard to its biochemistry, enzymatic mechanism, and biological function in the context of a prototypical HME complex.
1964年，阿尔弗雷及其同事提出，组蛋白的乙酰化和甲基化可能调节RNA合成，并描述了“完整蛋白质分子上发生的相对较小的组蛋白结构修饰，可能为开启或关闭沿染色体不同位点的RNA合成提供一种方式”[阿尔弗雷，V.，福克纳，R.，米尔施凯，A.（1964年）《美国国家科学院院刊》51，786]。五十年后，这一有先见之明的描述为组蛋白翻译后修饰（PTMs）的生物学作用提供了一个简单但概念上准确的模型。染色体的基本单位是核小体，双链DNA缠绕在组蛋白寡聚体周围。组蛋白的“尾巴”会进行翻译后修饰，这会以影响基因转录和复制可及性的方式改变核小体的物理性质。催化组蛋白PTMs添加和去除的酶，即组蛋白修饰酶（HMEs），存在于大型蛋白质复合物中，与DNA结合蛋白、ATP依赖性染色质重塑酶以及与翻译后修饰的组蛋白残基结合的表观遗传读取蛋白一起[阿罗史密斯，C. H.，邦特拉，C.，菲什，P. V.，李，K.，沙皮拉，M.（2012年）《自然药物发现综述》11，384 - 400]。HME复合物的活性与其他染色质相关复合物的活性相协调，这些复合物共同调节基因转录、DNA修复和DNA复制。在这种情况下，催化组蛋白PTMs添加和去除的酶是高度调控的紧密DNA获取机制的重要组成部分。为了全面了解HMEs的功能，将描述核小体的结构，即它们的天然底物。随后将针对每一类主要的HMEs，在典型HME复合物的背景下讨论其生物化学、酶促机制和生物学功能。
