DAXX in cancer: phenomena, processes, mechanisms and regulation

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.

A three layered histone epigenetics in breast cancer metastasis

“…Death domain-associated protein (DAXX) is a histone chaperone that recruits H3.3 histone variant [48]. DAXX interacts with Alpha Thalassemia/mental Retardation syndrome X-linked (ATRX), a chromatin remodeler [48][49][50]. Among the four domains of DAXX protein, the histone-binding domain HBD binds to the H3.3/H4 histones dimer.…”

MiR-25 Protects Against Apoptosis of Nucleus Pulposus Cells by Targeting SUMO2 in Intervertebral Disc Degeneration

“…to participate in posttranslational modi cation, regulate subcellular localization, and protein interactions and promote proteasome degradation (19,20). SUMOylation is involved in the regulation of apoptosis-associated signaling pathways, such as p53, death-associated protein (Daxx) and dynamin-related protein 1 (Drp1) (21)(22)(23). As a member of the SUMOs superfamily, SUMO2 is crucial for the degradation and apoptosis of NPCs through the activation of p53 signaling pathway (24,25).…”

Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements

“…Besides mutation and transcriptional downregulation, disruption of the H3.3 assembly has also implicated in cancers [38,[41][42][43][44][45]. For example, somatic mutations in the DAXX and ATRX, the histone chaperones for H3.3 deposition at telomeric and pericentromeric regions, were identified in pediatric glioblastoma tumors [46][47][48][49]. 43% of pancreatic neuroendocrine tumors (PanNETs) had mutations in genes that encode ATRX and DAXX [44].…”

“…Besides mutation and transcriptional downregulation, disruption of the H3.3 assembly has also been directly linked to cancers (Elsasser et al, 2011;Heaphy et al, 2011;Jiao et al, 2011;Schwartzentruber et al, 2012b;Sturm et al, 2012;Wu et al, 2012). For example, somatic mutations in the DAXX and ATRX, the histone chaperones for H3.3 deposition at telomeric and pericentromeric regions, were identified in pediatric glioblastoma tumors (Dyer et al, 2017;Mahmud and Liao, 2019;Newhart et al, 2013;Sarai et al, 2013). 43% of pancreatic neuroendocrine tumors (PanNETs) had mutations in genes that encode ATRX and DAXX (Heaphy et al, 2011).…”