Abstract
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.
Highlights
Oncogenic drivers promote tumorigenesis, cancer progression and resistance to therapy
As reviewed previously [15] and supported by nuclear magnetic resonance (NMR) spectroscopy-based experiments [16], the SUMO-SUMO-interacting motifs (SIMs) interaction is an important determinant for DAXX to bind a SUMOylated protein, which can be further stabilized by additional molecular interactions
Our analysis of a The Cancer Genome Atlas (TCGA) ovarian cancer dataset [59] shows that DAXX is highly upregulated in ovarian cancer samples compared with normal tissues (Figure 2A). These results suggest that DAXX upregulation might be a key step in ovarian tumorigenesis and disease progression and could be used as a diagnostic marker for ovarian cancers
Summary
As noted above, DAXX mutations in PanNETs frequently occur to regions encoding the folded 4HB and HBD domains (Figure 1) [22], suggesting that the loss of DAXX’s H3.3 chaperone function may lead to abnormal chromatin structures, epigenetic dysregulation and chromosome instability. A proapoptotic role for DAXX via the ASK1–JNK signaling pathway in the cytosol has been supported by multiple lines of evidence In these studies, apoptotic stimulation triggers DAXX’s nuclear export to activate the ASK1– JNK axis [96]; inhibiting this translocation by catalase [97], HSP27 [98,99,100], and DJ-1 (encoded by the PARK7 gene) [101,102] blocks apoptosis (Figure 3K). These observations suggest that the effects of DAXX’s recruitment to PML-NBs on cell survival or death may depend on cell-type and biological contexts It remains to be determined precisely how the localization of DAXX in PMLNBs regulates apoptosis vs cell survival. RASSF1A, a DAXX-binding protein, destabilizes MDM2 by disrupting the MDM2–DAXX–USP7
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