Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, 1333 Center Drive, Gainesville, FL 32610-0235, USA.
Nucleic Acids Res. 2019 Sep 5;47(15):7734-7752. doi: 10.1093/nar/gkz634.
DAXX displays complex biological functions. Remarkably, DAXX overexpression is a common feature in diverse cancers, which correlates with tumorigenesis, disease progression and treatment resistance. Structurally, DAXX is modular with an N-terminal helical bundle, a docking site for many DAXX interactors (e.g. p53 and ATRX). DAXX's central region folds with the H3.3/H4 dimer, providing a H3.3-specific chaperoning function. DAXX has two functionally critical SUMO-interacting motifs. These modules are connected by disordered regions. DAXX's structural features provide a framework for deciphering how DAXX mechanistically imparts its functions and how its activity is regulated. DAXX modulates transcription through binding to transcription factors, epigenetic modifiers, and chromatin remodelers. DAXX's localization in the PML nuclear bodies also plays roles in transcriptional regulation. DAXX-regulated genes are likely important effectors of its biological functions. Deposition of H3.3 and its interactions with epigenetic modifiers are likely key events for DAXX to regulate transcription, DNA repair, and viral infection. Interactions between DAXX and its partners directly impact apoptosis and cell signaling. DAXX's activity is regulated by posttranslational modifications and ubiquitin-dependent degradation. Notably, the tumor suppressor SPOP promotes DAXX degradation in phase-separated droplets. We summarize here our current understanding of DAXX's complex functions with a focus on how it promotes oncogenesis.
DAXX 具有复杂的生物学功能。值得注意的是，DAXX 过表达是多种癌症的共同特征，与肿瘤发生、疾病进展和治疗耐药性相关。从结构上看，DAXX 具有模块化的特征，其 N 端为螺旋束结构，是许多 DAXX 相互作用蛋白（如 p53 和 ATRX）的结合位点。DAXX 的中心区域与 H3.3/H4 二聚体折叠，提供 H3.3 特异性的伴侣功能。DAXX 有两个功能上关键的 SUMO 相互作用基序。这些模块通过无序区域连接。DAXX 的结构特征为阐明 DAXX 如何发挥其功能以及其活性如何受到调节提供了一个框架。DAXX 通过与转录因子、表观遗传修饰物和染色质重塑剂结合来调节转录。DAXX 在 PML 核体中的定位也在转录调控中发挥作用。DAXX 调节的基因可能是其生物学功能的重要效应物。H3.3 的沉积及其与表观遗传修饰物的相互作用可能是 DAXX 调节转录、DNA 修复和病毒感染的关键事件。DAXX 与其伴侣之间的相互作用直接影响细胞凋亡和信号转导。DAXX 的活性受到翻译后修饰和泛素依赖性降解的调节。值得注意的是，肿瘤抑制因子 SPOP 促进 DAXX 在相分离液滴中的降解。我们在此总结了我们对 DAXX 复杂功能的现有认识，重点介绍了它促进致癌作用的机制。
