Chopra Anand, Feldman Michal, Levy Dan
The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
Exp Mol Med. 2025 Mar;57(3):533-544. doi: 10.1038/s12276-025-01423-2. Epub 2025 Mar 18.
Transcription is regulated by an intricate and extensive network of regulatory factors that impinge upon target genes. This process involves crosstalk between a plethora of factors that include chromatin structure, transcription factors and posttranslational modifications (PTMs). Among PTMs, lysine methylation has emerged as a key transcription regulatory PTM that occurs on histone and non-histone proteins, and several enzymatic regulators of lysine methylation are attractive targets for disease intervention. SET domain-containing protein 6 (SETD6) is a mono-methyltransferase that promotes the methylation of multiple transcription factors and other proteins involved in the regulation of gene expression programs. Many of these SETD6 substrates, such as the canonical SETD6 substrate RELA, are linked to cellular pathways that are highly relevant to human health and disease. Furthermore, SETD6 regulates numerous cancerous phenotypes and guards cancer cells from apoptosis. In the past 15 years, our knowledge of SETD6 substrate methylation and the biological roles of this enzyme has grown immensely. Here we provide a comprehensive overview of SETD6 that will enhance our understanding of this enzyme's role in chromatin and in selective transcriptional control, the contextual biological roles of this enzyme, and the molecular mechanisms and pathways in which SETD6 is involved, and we highlight the major trends in the SETD6 field.
转录受一个复杂且广泛的调控因子网络调节，这些调控因子作用于靶基因。这个过程涉及众多因素之间的相互作用，包括染色质结构、转录因子和翻译后修饰（PTM）。在翻译后修饰中，赖氨酸甲基化已成为一种关键的转录调控性翻译后修饰，它发生在组蛋白和非组蛋白上，并且赖氨酸甲基化的几种酶促调节因子是疾病干预的有吸引力的靶点。含SET结构域蛋白6（SETD6）是一种单甲基转移酶，可促进多种转录因子和其他参与基因表达程序调控的蛋白质的甲基化。许多SETD6底物，如典型的SETD6底物RELA，都与与人类健康和疾病高度相关的细胞途径有关。此外，SETD6调节多种癌性表型，并保护癌细胞免于凋亡。在过去的15年里，我们对SETD6底物甲基化以及该酶的生物学作用的了解有了极大的增长。在这里，我们对SETD6进行全面概述，这将增进我们对该酶在染色质和选择性转录控制中的作用、该酶的背景生物学作用以及SETD6所涉及的分子机制和途径的理解，并且我们突出了SETD6领域的主要趋势。
