Gambetta Maria Cristina, Müller Jürg
MPI of Biochemistry, Chromatin and Chromosome Biology, Am Klopferspitz 18, 82152, Martinsried, Germany.
Chromosoma. 2015 Dec;124(4):429-42. doi: 10.1007/s00412-015-0513-1. Epub 2015 Apr 18.
O-linked β-N-Acetylglucosamine (O-GlcNAc) is a posttranslational modification that is catalyzed by O-GlcNAc transferase (Ogt) and found on a plethora of nuclear and cytosolic proteins in animals and plants. Studies in different model organisms revealed that while O-GlcNAc is required for selected processes in Caenorhabditis elegans and Drosophila, it has evolved to become required for cell viability in mice, and this has challenged investigations to identify cellular functions that critically require this modification in mammals. Nevertheless, a principal cellular process that engages O-GlcNAcylation in all of these species is the regulation of gene transcription. Here, we revisit several of the primary experimental observations that led to current models of how O-GlcNAcylation affects gene expression. In particular, we discuss the role of the stable association of Ogt with the transcription factors Hcf1 and Tet, the two main Ogt-interacting proteins in nuclei of mammalian cells. We also critically evaluate the evidence that specific residues on core histones, including serine 112 of histone 2B (H2B-S112), are O-GlcNAcylated in vivo and discuss possible physiological effects of these modifications. Finally, we review our understanding of the role of O-GlcNAcylation in Drosophila, where recent studies suggest that the developmental defects in Ogt mutants are all caused by lack of O-GlcNAcylation of a single transcriptional regulator, the Polycomb repressor protein Polyhomeotic (Ph). Collectively, this reexamination of the experimental evidence suggests that a number of recently propagated models about the role of O-GlcNAcylation in transcriptional control should be treated cautiously.
O-连接的β-N-乙酰葡糖胺（O-GlcNAc）是一种翻译后修饰，由O-GlcNAc转移酶（Ogt）催化，存在于动植物的大量核蛋白和胞质蛋白上。对不同模式生物的研究表明，虽然O-GlcNAc在秀丽隐杆线虫和果蝇的特定过程中是必需的，但在小鼠中它已进化为细胞存活所必需的，这给鉴定哺乳动物中严格需要这种修饰的细胞功能的研究带来了挑战。然而，在所有这些物种中涉及O-GlcNAc化的一个主要细胞过程是基因转录的调控。在这里，我们重新审视了一些主要的实验观察结果，这些结果导致了目前关于O-GlcNAc化如何影响基因表达的模型。特别是，我们讨论了Ogt与转录因子Hcf1和Tet稳定结合的作用，这是哺乳动物细胞核中两个主要的与Ogt相互作用的蛋白。我们还严格评估了核心组蛋白上特定残基（包括组蛋白2B的丝氨酸112，即H2B-S112）在体内被O-GlcNAc化的证据，并讨论了这些修饰可能的生理效应。最后，我们回顾了我们对O-GlcNAc化在果蝇中的作用的理解，最近的研究表明，Ogt突变体中的发育缺陷都是由单个转录调节因子——多梳抑制蛋白多梳同源蛋白（Ph）缺乏O-GlcNAc化引起的。总体而言，对实验证据的重新审视表明，一些最近传播的关于O-GlcNAc化在转录控制中作用的模型应谨慎对待。
