Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
The Institute of Cancer Research, London, UK.
Nat Struct Mol Biol. 2024 Jan;31(1):11-22. doi: 10.1038/s41594-023-01173-7. Epub 2024 Jan 12.
The human silencing hub (HUSH) complex is an epigenetic repressor complex whose role has emerged as an important guardian of genome integrity. It protects the genome from exogenous DNA invasion and regulates endogenous retroelements by recruiting histone methyltransferases catalyzing histone 3 lysine 9 trimethylation (H3K9me3) and additional proteins involved in chromatin compaction. In particular, its regulation of transcriptionally active LINE1 retroelements, by binding to and neutralizing LINE1 transcripts, has been well characterized. HUSH is required for mouse embryogenesis and is associated with disease, in particular cancer. Here we provide insights into the structural and biochemical features of the HUSH complex. Furthermore, we discuss the molecular mechanisms by which the HUSH complex is recruited to specific genomic regions and how it silences transcription. Finally, we discuss the role of HUSH complex members in mammalian development, antiretroviral immunity, and diseases such as cancer.
人类沉默枢纽 (HUSH) 复合物是一种表观遗传抑制复合物，其作用已成为基因组完整性的重要保护者。它通过招募组蛋白甲基转移酶催化组蛋白 3 赖氨酸 9 三甲基化 (H3K9me3) 和其他参与染色质紧缩的蛋白质，保护基因组免受外源 DNA 的入侵并调节内源性逆转录元件。特别是，它通过与 LINE1 转录本结合并中和 LINE1 转录本来调节转录活跃的 LINE1 逆转录元件，这已得到很好的描述。HUSH 对于小鼠胚胎发生是必需的，并且与疾病，特别是癌症有关。在这里，我们提供了对 HUSH 复合物的结构和生化特征的深入了解。此外，我们讨论了 HUSH 复合物被招募到特定基因组区域的分子机制以及它如何沉默转录。最后，我们讨论了 HUSH 复合物成员在哺乳动物发育、抗逆转录病毒免疫以及癌症等疾病中的作用。
