DAXX
Death domain-associated protein 6 (Daxx) (hDaxx) (ETS1-associated protein 1) (EAP1) (Fas death domain-associated protein) [BING2] [DAP6]
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The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adult
- Aged
- Aged, 80 and over
- Aging
- Brain
- Co-Repressor Proteins
- Humans
- Middle Aged
- Molecular Chaperones
- Nuclear Proteins
- Telomere Homeostasis
- X-linked Nuclear Protein
Keywords
- ATRX
- DAXX
- aging
- gene and protein expressions
- human brain tissues
- telomere length
Death-associated protein 6 (DAXX) is a ubiquitous protein implicated in various cellular processes such as apoptosis, tumorigenesis, development and transcription. The role of DAXX is however ambiguous and many contradictory results regarding its function in apoptosis upon various cellular stresses are described in the literature. In order to have a better understanding of the role of DAXX throughout the entire organism under physiological stress conditions, we have characterized the mRNA levels, protein expression and the proteolytic processing of DAXX in the normal aging process in peripheral organs and brain regions in C57BL/6 male mice. Overall, Daxx mRNA expression decreases with aging in the liver, kidney, heart, cortex and cerebellum. In contrast, an increase is observed in the striatum. The protein expression of DAXX and of its proteolytic fragments increases with aging in the kidney, heart and cortex. In liver and spleen, no changes are observed while in the striatum and cerebellum, certain forms increase and others decrease with age, suggesting that the functions of DAXX may be cell type dependent. This study provides important details regarding the expression and post-translational modifications of DAXX in aging in the entire organism and provides reference data for the deregulation observed in age-associated diseases.
MeSH Terms
- Aging
- Animals
- Brain
- Carrier Proteins
- Co-Repressor Proteins
- Gene Expression Regulation, Developmental
- Intracellular Signaling Peptides and Proteins
- Male
- Mice
- Mice, Inbred C57BL
- Molecular Chaperones
- Nuclear Proteins
- Organ Specificity
- Viscera
Keywords
- Aging
- Brain region
- C57BL/6 mice
- Caspase
- DAXX
- Peripheral organs
Oncogene-induced senescence is a permanent cell cycle arrest characterized by extensive chromatin reorganization. Here, we investigated the specific targeting and dynamics of histone H3 variants in human primary senescent cells. We show that newly synthesized epitope-tagged H3.3 is incorporated in senescent cells but does not accumulate in senescence-associated heterochromatin foci (SAHF). Instead, we observe that new H3.3 colocalizes with its specific histone chaperones within the promyelocytic leukemia nuclear bodies (PML-NBs) and is targeted to PML-NBs in a DAXX-dependent manner both in proliferating and senescent cells. We further show that overexpression of DAXX enhances targeting of H3.3 in large PML-NBs devoid of transcriptional activity and promotes the accumulation of HP1, independently of H3K9me3. Loss of H3.3 from pericentromeric heterochromatin upon DAXX or PML depletion suggests that the targeting of H3.3 to PML-NBs is implicated in pericentromeric heterochromatin organization. Together, our results underline the importance of the replication-independent chromatin assembly pathway for histone replacement in non-dividing senescent cells and establish PML-NBs as important regulatory sites for the incorporation of new H3.3 into chromatin.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Cell Line
- Cell Nucleus
- Cell Proliferation
- Cellular Senescence
- Chromatin Assembly and Disassembly
- Co-Repressor Proteins
- DNA Helicases
- DNA, Satellite
- Euchromatin
- Heterochromatin
- Histones
- Humans
- Leukemia, Promyelocytic, Acute
- Molecular Chaperones
- Nuclear Proteins
- Primary Cell Culture
- X-linked Nuclear Protein
Keywords
- DAXX
- H3.3
- PML-NBs
- chromatin dynamics
- senescence
Mouse ovarian surface epithelium (OSE) is a single layer of cubodial epithelial cells that covers the ovary surface and is involved in regulating the secretion and transport of 17β-hydroxysteroid dehydrogenase. Recently, OSE cells have attracted particular interest as a major source of ovarian cancer. Death-associated protein DAXX along with PML (promyelocytic leukemia protein) nuclear bodies (PML-NBs) reportedly play roles in transcriptional regulation and apoptosis. However, little is known regarding a role for DAXX in mOSE cells. In this study, we both over-expressed DAXX and depleted DAXX in primary mOSE cells. We found that Daxx deletion accelerated senescence in a p53/p21-dependent manner and promoted DNA damage by interacting with PML bodies without affecting cell cycle progression. These results suggest that DAXX may transform mOSE cells to an ovarian oncogenic phenotype and may be an anti-cancer target.
MeSH Terms
- Animals
- Carcinoma, Ovarian Epithelial
- Carrier Proteins
- Cell Cycle
- Cellular Senescence
- Co-Repressor Proteins
- DNA Damage
- Epithelial Cells
- Female
- Gene Deletion
- Gene Expression
- Gene Silencing
- Humans
- Intracellular Signaling Peptides and Proteins
- Mice
- Molecular Chaperones
- Neoplasms, Glandular and Epithelial
- Nuclear Proteins
- Oncogene Protein p21(ras)
- Ovarian Neoplasms
- Ovary
- Promyelocytic Leukemia Protein
- Transcription Factors
- Tumor Suppressor Protein p53
- Tumor Suppressor Proteins
Keywords
- CCAAT/enhancer-binding protein beta
- CEBPβ
- DAXX
- DNA
- DNA damage
- DTT
- EDTA
- EGF
- ETS1
- FBS
- GFP
- ITS
- Insulin–Transferrin–Selenium
- Ovarian surface epithelium
- PAX5
- PBS
- PCR
- PI
- PML
- PML-NBs
- PML-oncogenic domains
- PODs
- SA-β -gal
- Senescence
- TUNEL
- TdT-mediated dUTP Nick-End Labeling
- dNTP
- death-associated protein
- deoxyribonucleic acid
- deoxyribonucleotide triphosphate
- dithiothreitol
- epidermal growth factor
- ethylenediamine tetraacetic acid
- fetal bovine serum
- green fluorescent protein
- mOSE
- mouse ovarian surface epithelium
- paired box 5
- phosphate-buffered saline
- polymerase chain reaction
- promyelocytic leukemia protein
- promyelocytic leukemia protein nuclear bodies
- propidium iodide
- senescence-associated β-galactosidase
- v-ets erythroblastosis virus E26 oncogene homolog 1 (avian)