The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3

Abstract

The histone variant H3.3 marks active chromatin by replacing the conventional histone H3.1. In this study, we investigate the detailed mechanism of H3.3 replication-independent deposition. We found that the death domainassociated protein DAXX and the chromatin remodeling factor ATRX (a-thalassemia/mental retardation syndrome protein) are specifically associated with the H3.3 deposition machinery. Bacterially expressed DAXX has a marked binding preference for H3.3 and assists the deposition of (H3.3-H4) 2 tetramers on naked DNA, thus showing that DAXX is a H3.3 histone chaperone. In DAXX-depleted cells, a fraction of H3.3 was found associated with the replication-dependent machinery of deposition, suggesting that cells adapt to the depletion. The reintroduced DAXX in these cells colocalizes with H3.3 into the promyelocytic leukemia protein (PML) bodies. Moreover, DAXX associates with pericentric DNA repeats, and modulates the transcription from these repeats through assembly of H3.3 nucleosomes. These findings establish a new link between the PML bodies and the regulation of pericentric DNA repeat chromatin structure. Taken together, our data demonstrate that DAXX functions as a bona fide histone chaperone involved in the replication-independent deposition of H3.3.[Keywords: Histone variant; H3.3; histone chaperone; PML-NBs] Supplemental material is available at http://www.genesdev.org.

Germinal center kinases in immune regulation

“…33 As a novel histone chaperone and a product of an interferon-c-induced gene, Daxx has been extensively implicated in virus infection and T-cell activation. [34][35][36][37][38][39][40][41][42][43] Recent studies demonstrated that MST1 and Daxx interact with each other to mediate interferon-c-induced apoptosis in microglia, which plays a critical role during inflammation. 44 In this process, Daxx directly binds to MST1 and regulates its homooligomerization, activation and nuclear translocation.…”

The double face of the histone variant H3.3

“…Unexpectedly, enrichment of H3.3 was recently also observed in regions of the genome that should be transcriptionally silent. Indeed, H3.3 accumulation is found at telomeres and pericentric heterochromatin in mouse ES cells and mouse embryonic fibroblasts (MEF), respectively ( Figure 3) [24,[48][49][50]. Of note, these accumulations could either reflect more loading or less removal of H3.3 at these loci as compared with other places in the genome.…”

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

“…13 ATRX and DAXX form a dimer that acts as a histone chaperone to deposit histone variant H3.3 to GC-rich regions of the genome, including the telomeres, and plays important roles in maintaining telomere stability. [14][15][16] It is hypothesized that dysfunction of the dimer leads to telomere instability, increased telomere homologous recombination, and ultimately, alternative lengthening of telomeres. Subsequent studies have reported frequent ATRX loss (but not DAXX loss) in astrocytoma, leiomyosarcoma, dedifferentiated liposarcoma and other tumor types, and the loss of ATRX has been highly correlated with the alternative lengthening of telomeres phenotype.…”