The PML-Interacting Protein DAXX: Histone Loading Gets into the Picture

Abstract

The promyelocytic leukemia (PML) protein has been implicated in regulation of multiple key cellular functions, from transcription to calcium homeostasis. PML pleiotropic role is in part related to its ability to localize to both the nucleus and cytoplasm. In the nucleus, PML is known to regulate gene transcription, a role linked to its ability to associate with transcription factors as well as chromatin-remodelers. A new twist came from the discovery that the PML-interacting protein death-associated protein 6 (DAXX) acts as chaperone for the histone H3.3 variant. H3.3 is found enriched at active genes, centromeric heterochromatin, and telomeres, and has been proposed to act as important carrier of epigenetic information. Our recent work has implicated DAXX in regulation of H3.3 loading and transcription in the central nervous system (CNS). Remarkably, driver mutations in H3.3 and/or its loading machinery have been identified in brain cancer, thus suggesting a role for altered H3.3 function/deposition in CNS tumorigenesis. Aberrant H3.3 deposition may also play a role in leukemia pathogenesis, given DAXX role in PML-RARα-driven transformation and the identification of a DAXX missense mutation in acute myeloid leukemia. This review aims to critically discuss the existing literature and propose new avenues for investigation.

Impact of Adenovirus E4-ORF3 Oligomerization and Protein Localization on Cellular Gene Expression

“…Several cellular proteins sequestered into E4-ORF3 nuclear tracks regulate cellular gene expression. Daxx generally represses gene regulation through chromatin remodeling although is may serve as a transcriptional activator in certain cases [ 53 ]. TRIM33 serves as a multifunctional coregulator of gene expression, influencing TGFβ signaling and other pathways [ 38 , 39 ].…”

A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS

“…In this respect, a recent study implicated PML in the maintenance of heterochromatin integrity via modulation of H3K9me3/H3K27me3 balance at heterochromatic PML-associated domains (PADs). Specifically, PML loss leads to a shift of histone methylation from H3K9me3 to H3K27me3 at PADs (Delbarre et al, 2017), potentially linked to its ability to interact with the H3.3 chaperone complex ATRX/DAXX (Salomoni, 2013;Delbarre et al, 2017). It would be interesting to determine whether H3K27me3-enriched PADs relocate to NL upon PML downregulation/loss.…”

Epigenetic dysregulation and poorer prognosis in DAXX-deficient pancreatic neuroendocrine tumours

“…2013 ). Notably, H3.3 is mutated in paediatric glioblastoma and bone tumours, and H3.3 mutations are often associated with changes in global DNA methylation ( Salomoni 2013 , Maze et al . 2014 ).…”