Alternative titles; symbols
HGNC Approved Gene Symbol: DAXX
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38) : 6:33,318,558-33,322,959 (from NCBI)
Yang et al. (1997) performed yeast 2-hybrid screening to identify novel proteins that interact with the apoptosis antigen Fas (134637). They cloned a mouse gene that they called Daxx (Fas death domain-associated protein).
Kiriakidou et al. (1997) cloned the human and monkey orthologs of Daxx. Human DAXX encodes a 740-amino acid polypeptide containing a nuclear localization signal. The protein is highly acidic (pI = 4.9) due to extended glutamic acid-rich domains. Northern blot analysis revealed a single 2.6-kb mRNA expressed in all human adult and fetal tissues assayed.
By EST database analysis, followed by PCR of a human B lymphoblastoid cell line cDNA library, Herberg et al. (1998) cloned DAXX, which they called BING2. Northern blot analysis detected a dominant 3-kb transcript in all tissues examined, a 1.7-kb transcript in placenta and pancreas, and an approximately 8-kb transcript in heart and skeletal muscle.
Functional analyses by Yang et al. (1997) demonstrated that Daxx binds to the Fas death domain and enhances Fas-mediated apoptosis. The authors suggested that DAXX and FADD (602457) define 2 distinct apoptotic pathways downstream of Fas.
Using immunoprecipitation-kinase analysis, Chang et al. (1998) showed that activity of the JNK kinase kinase ASK1 (MAP3K5; 602448), but not of TAK1 (MAP3K7; 602614) or an ASK1 lys709-to-arg mutant, is potentiated by coexpression with DAXX or the JNK activation domain (amino acids 501 to 625) of DAXX. FAS activation was found to enhance endogenous ASK1 activity. Yeast 2-hybrid analysis established that ASK1 interacts directly with DAXX but not FAS, indicating that DAXX acts as a bridge between FAS and ASK1. Chang et al. (1998) concluded that the DAXX-ASK1 connection provides a mechanism for caspase-independent activation of JNK by FAS and perhaps other stimuli.
Raoul et al. (2002) showed that Fas triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS; 163731) mediated by p38 kinase (600289). ASK1 and Daxx act upstream of p38 in the Fas signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD/caspase-8 (601763) pathway were needed for motor neuron cell death. No evidence for involvement of the Fas/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing amyotrophic lateral sclerosis (ALS; 105400)-linked SOD1 (147450) mutations displayed increased susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002) emphasized that this signaling pathway was unique to motor neurons and suggested that these cell pathways may contribute to motor neuron loss in ALS. Raoul et al. (2006) reported that exogenous NO triggered expression of Fas ligand (FASL; 134638) in cultured motoneurons. In motoneurons from ALS model mice with mutations in the SOD1 gene, this upregulation resulted in activation of Fas, leading through Daxx and p38 to further NO synthesis. The authors suggested that chronic low-activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS.
Lin and Shih (2002) found that MSP58 (609504) interacted with DAXX in vitro and in vivo, and MSP58 overexpression correlated with sequestration of DAXX from a diffuse nuclear distribution to the nucleolus. MSP58 overexpression relieved DAXX-mediated transcriptional repression. Lin and Shih (2002) concluded that translocation of the MSP58-DAXX complex to the nucleolus results in derepression of DAXX-regulated genes.
In order to clarify the role of DAXX in IFNA (147660)/IFNB (147640)-mediated suppression of B-cell development and apoptosis, Muromoto et al. (2004) used a yeast 2-hybrid screen and identified DMAP1 (605077) as a DAXX-interacting protein. Immunoprecipitation and Western blot analysis with DAXX mutants showed that the N terminus of DAXX interacts with the C terminus of DMAP. Immunoblot analysis and confocal microscopy demonstrated that the DAXX-DMAP complex interacts with DNMT1 (126375) in the nucleus. Transient expression of DAXX or DMAP1 caused repression of glucocorticoid receptor (GCCR; 138040)-mediated transcription. Muromoto et al. (2004) concluded that the linkage between DAXX and DNMT1 forms an efficient transcription repression complex in the nucleus.
Junn et al. (2005) found that DJ1 (602533) interacted with DAXX. Overexpression of DJ1 protected cells from DAXX/ASK1-induced apoptosis by sequestering DAXX in the nucleus and preventing its activation of cytoplasmic ASK1. DJ1 carrying a Parkinson disease-associated mutation (L166P; 602533.0002) was unable to interact with DAXX or protect cells from DAXX/ASK1-induced apoptosis.
Elsasser et al. (2015) showed that the replacement histone variant H3.3 (601128) is enriched at class I and class II endogenous retroviral elements (ERVs), notably those of the early transposon/MusD family and intracisternal A-type particles. Deposition at a subset of these elements is dependent on the H3.3 chaperone complex containing ATRX (300032) and DAXX. Elsasser et al. (2015) demonstrated that recruitment of DAXX, H3.3, and KAP1 (TRIM28; 601742) to ERVs is codependent and occurs upstream of ESET (SETDB1; 604396), linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of intracisternal A-type particles. Elsasser et al. (2015) concluded that their study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells.
DNA damage results in acetylation of lysines in the C-terminal domain of the proapoptotic transcriptional activator p53 (TP53; 191170). Wang et al. (2016) found that acidic domain-containing proteins, including SET (600960), DAXX, PELP1 (609455), and VPRBP (DCAF1; 617259), bound the deacetylated C-terminal domain of p53 in human cell lines and repressed p53 function. SET, VPRBP, DAXX, and PELP1 also interacted with the deacetylated, but not acetylated, lysine-rich domain of histone H3 (see 602810).
Pancreatic Neuroendocrine Tumors
Jiao et al. (2011) explored the genetic basis of pancreatic neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1 (613733), and 43% had mutations in genes encoding either of the 2 subunits of a transcription/chromatin remodeling complex consisting of DAXX and ATRX (300032). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. Jiao et al. (2011) also found mutations in genes in the mTOR (601231) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatments with mTOR inhibitors.
Heaphy et al. (2011) evaluated telomere status in PanNETs in which ATRX and DAXX mutational status had been determined through Sanger sequencing. Telomere-specific FISH revealed that 25 of 41 (61%) PanNETs displayed large, ultrabright telomere FISH signals, a nearly universal feature of the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres. ATRX and DAXX gene mutations both were significantly correlated with alternative lengthening of telomeres (ALT) positivity (P less than 0.008 for each gene). All 19 (100%) PanNETs with ATRX or DAXX gene mutations were ALT-positive, whereas 6 of 20 cases without detectable mutations were ALT-positive. To ascertain whether ATRX and DAXX gene mutations might be more generally associated with the ALT phenotype, Heaphy et al. (2011) examined 439 tumors of other types and found a strong correlation between inactivation of ATRX or DAXX and the ALT phenotype in unrelated tumor types.
Pediatric Glioblastoma
Schwartzentruber et al. (2012) sequenced the exomes of 48 pediatric glioblastoma (137800) samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodeling pathway were identified in 44% of tumors (21 of 48). Recurrent mutations in H3F3A (601128), which encodes the replication-independent histone-3 variant H3.3, were observed in 31% of tumors, and led to amino acid substitutions at 2 critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory posttranslational modifications. Mutations in ATRX and DAXX, encoding 2 subunits of a chromatin remodeling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumors harboring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to glioblastoma multiforme and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. Schwartzentruber et al. (2012) stated that this was the first report to highlight recurrent mutations in a regulatory histone in humans, and that their data suggested that defects of the chromatin architecture underlie pediatric and young adult glioblastoma multiforme pathogenesis.
Kiriakidou et al. (1997) showed that the DAXX gene contains 7 exons spanning approximately 3.5 kb.
Herberg et al. (1998) determined that the DAXX gene contains 8 exons, including a noncoding first exon.
Crystal Structure
Elsasser et al. (2012) reported the crystal structures of the DAXX histone-binding domain with a histone H3.3 (see 601128)-H4 (see 602822) dimer, including mutants within DAXX and H3.3, together with in vitro and in vivo functional studies that elucidated the principles underlying H3.3 recognition specificity. Occupying 40% of the histone surface-accessible area, DAXX wraps around the H3.3-H4 dimer, with complex formation accompanied by structural transitions in the H3.3-H4 histone fold. DAXX uses an extended alpha-helical conformation to compete with major interhistone, DNA, and ASF1 interaction sites. Elsasser et al. (2012) concluded that their structural studies identified recognition elements that read out H3.3-specific residues, and functional studies addressed the contribution of gly90 in H3.3 and glu225 in DAXX to chaperone-mediated H3.3 variant recognition specificity.
Kiriakidou et al. (1997) used somatic cell hybrid panels and fluorescence in situ hybridization to map the DAXX gene to human chromosome 6p21.3, a region containing the HLA and putative autoimmune disease genes.
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Elsasser, S. J., Huang, H., Lewis, P. W., Chin, J. W., Allis, C. D., Patel, D. J. DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition. Nature 491: 560-565, 2012. [PubMed: 23075851] [Full Text: https://doi.org/10.1038/nature11608]
Elsasser, S. J., Noh, K.-M., Diaz, N., Allis, C. D., Banaszynski, L. A. Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature 522: 240-244, 2015. [PubMed: 25938714] [Full Text: https://doi.org/10.1038/nature14345]
Heaphy, C. M., de Wilde, R. F., Jiao, Y., Klein, A. P., Edil, B. H., Shi, C., Bettegowda, C., Rodriguez, F. J., Eberhart, C. G., Hebbar, S., Offerhaus, G. J., McLendon, R., and 13 others. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333: 425 only, 2011. [PubMed: 21719641] [Full Text: https://doi.org/10.1126/science.1207313]
Herberg, J. A., Beck, S., Trowsdale, J. TAPASIN, DAXX, RGL2, HKE2, and four new genes (BING 1, 3 to 5) form a dense cluster at the centromeric end of the MHC. J. Molec. Biol. 277: 839-857, 1998. [PubMed: 9545376] [Full Text: https://doi.org/10.1006/jmbi.1998.1637]
Jiao, Y., Shi, C., Edil, B. H., de Wilde, R. F., Klimstra, D. S., Maitra, A., Schulick, R. D., Tang, L. H., Wolfgang, C. L., Choti, M. A., Velculescu, V. E., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Hruban, R. H., Papadopoulos, N. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331: 1199-1203, 2011. [PubMed: 21252315] [Full Text: https://doi.org/10.1126/science.1200609]
Junn, E., Taniguchi, H., Jeong, B. S., Zhao, X., Ichijo, H., Mouradian, M. M. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc. Nat. Acad. Sci. 102: 9691-9696, 2005. [PubMed: 15983381] [Full Text: https://doi.org/10.1073/pnas.0409635102]
Kiriakidou, M., Driscoll, D. A., Lopez-Guisa, J. M., Strauss, J. F., III. Cloning and expression of primate Daxx cDNAs and mapping of the human gene to chromosome 6p21.3 in the MHC region. DNA Cell Biol. 16: 1289-1298, 1997. [PubMed: 9407001] [Full Text: https://doi.org/10.1089/dna.1997.16.1289]
Lin, D.-Y., Shih, H.-M. Essential role of the 58-kDa microspherule protein in the modulation of Daxx-dependent transcriptional repression as revealed by nucleolar sequestration. J. Biol. Chem. 277: 25446-25456, 2002. [PubMed: 11948183] [Full Text: https://doi.org/10.1074/jbc.M200633200]
Muromoto, R., Sugiyama, K., Takachi, A., Imoto, S., Sato, N., Yamamoto, T., Oritani, K., Shimoda, K., Matsuda, T. Physical and functional interactions between Daxx and DNA methyltransferase 1-associated protein, DMAP1. J. Immun. 172: 2985-2993, 2004. [PubMed: 14978102] [Full Text: https://doi.org/10.4049/jimmunol.172.5.2985]
Raoul, C., Buhler, E., Sadeghi, C., Jacquier, A., Aebischer, P., Pettmann, B., Henderson, C. E., Haase, G. Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL. Proc. Nat. Acad. Sci. 103: 6007-6012, 2006. [PubMed: 16581901] [Full Text: https://doi.org/10.1073/pnas.0508774103]
Raoul, C., Estevez, A. G., Nishimune, H., Cleveland, D. W., deLapeyriere, O., Henderson, C. E., Hasse, G., Pettmann, B. Motoneuron death triggered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD1 mutations. Neuron 35: 1067-1083, 2002. [PubMed: 12354397] [Full Text: https://doi.org/10.1016/s0896-6273(02)00905-4]
Schwartzentruber, J., Korshunov, A, Liu, X.-Y., Jones, D. T. W., Pfaff, E., Jacob, K., Sturm, D., Fontebasso, A. M., Quang, D.-A. K., Tonjes, M., Hovestadt, V., Albrecht, S., and 50 others. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482: 226-231, 2012. Note: Erratum: Nature 484: 130 only, 2012. [PubMed: 22286061] [Full Text: https://doi.org/10.1038/nature10833]
Wang, D., Kon, N., Lasso, G., Leng, W., Zhu, W.-G., Qin, J., Honig, B., Gu, W. Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature 538: 118-122, 2016. [PubMed: 27626385] [Full Text: https://doi.org/10.1038/nature19759]
Yang, X., Khosravi-Far, R., Chang, H. Y., Baltimore, D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 89: 1067-1076, 1997. [PubMed: 9215629] [Full Text: https://doi.org/10.1016/s0092-8674(00)80294-9]