DAXX

Summary

DAXX (death domain associated protein, HGNC:2681) is a protein-coding gene on chromosome 6p21.32, encoding Death domain-associated protein 6 (Q9UER7). Transcription corepressor known to repress transcriptional potential of several sumoylated transcription factors. It is a selective cancer dependency (DepMap: 26.1% of cell lines).

This gene encodes a multifunctional protein that resides in multiple locations in the nucleus and in the cytoplasm. It interacts with a wide variety of proteins, such as apoptosis antigen Fas, centromere protein C, and transcription factor erythroblastosis virus E26 oncogene homolog 1. In the nucleus, the encoded protein functions as a potent transcription repressor that binds to sumoylated transcription factors. Its repression can be relieved by the sequestration of this protein into promyelocytic leukemia nuclear bodies or nucleoli. This protein also associates with centromeres in G2 phase. In the cytoplasm, the encoded protein may function to regulate apoptosis. The subcellular localization and function of this protein are modulated by post-translational modifications, including sumoylation, phosphorylation and polyubiquitination. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1616 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 100 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• Cancer dependency (DepMap): dependent in 26.1% of screened cell lines
• MANE Select transcript: NM_001141969

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2681
Approved symbol	DAXX
Name	death domain associated protein
Location	6p21.32
Locus type	gene with protein product
Status	Approved
Aliases	DAP6
Ensembl gene	ENSG00000204209
Ensembl biotype	protein_coding
OMIM	603186
Entrez	1616

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 27 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000266000, ENST00000374542, ENST00000414083, ENST00000446403, ENST00000446511, ENST00000468536, ENST00000477162, ENST00000490173, ENST00000498030, ENST00000620164, ENST00000706094, ENST00000859774, ENST00000859775, ENST00000859776, ENST00000859777, ENST00000859778, ENST00000859779, ENST00000859780, ENST00000859781, ENST00000932661, ENST00000932662, ENST00000932663, ENST00000932664, ENST00000932665, ENST00000932666, ENST00000932667, ENST00000932668, ENST00000932669, ENST00000932670, ENST00000932671, ENST00000941963

RefSeq mRNA: 4 — MANE Select: NM_001141969 NM_001141969, NM_001141970, NM_001254717, NM_001350

CCDS: CCDS4776, CCDS59008, CCDS93890

Canonical transcript exons

ENST00000374542 — 8 exons

Exon	Start	End
ENSE00001648385	33319380	33319854
ENSE00001722505	33318997	33319219
ENSE00001815438	33318558	33318802
ENSE00001937709	33322862	33322959
ENSE00003491811	33320736	33321567
ENSE00003587496	33320380	33320591
ENSE00003691755	33320011	33320224
ENSE00003820989	33321719	33321977

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 96.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.0769 / max 335.8124, expressed in 1804 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73155	13.3250	1799
73151	2.5241	625
73153	0.1407	39
73152	0.0573	16
73154	0.0299	6

Top tissues by expression

145 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.45	gold quality
lymph node	UBERON:0000029	95.63	gold quality
vermiform appendix	UBERON:0001154	94.29	gold quality
spleen	UBERON:0002106	94.29	gold quality
ventricular zone	UBERON:0003053	94.06	gold quality
stromal cell of endometrium	CL:0002255	93.83	gold quality
blood	UBERON:0000178	93.76	gold quality
left testis	UBERON:0004533	93.64	gold quality
left adrenal gland	UBERON:0001234	93.47	gold quality
left uterine tube	UBERON:0001303	93.46	gold quality
left adrenal gland cortex	UBERON:0035825	93.43	gold quality
right testis	UBERON:0004534	93.42	gold quality
islet of Langerhans	UBERON:0000006	93.41	gold quality
leukocyte	CL:0000738	93.37	gold quality
right adrenal gland	UBERON:0001233	93.26	gold quality
sural nerve	UBERON:0015488	93.24	gold quality
embryo	UBERON:0000922	93.23	gold quality
ganglionic eminence	UBERON:0004023	93.23	gold quality
monocyte	CL:0000576	93.15	gold quality
testis	UBERON:0000473	93.10	gold quality
right adrenal gland cortex	UBERON:0035827	92.86	gold quality
adrenal gland	UBERON:0002369	92.69	gold quality
tonsil	UBERON:0002372	92.43	gold quality
myometrium	UBERON:0001296	92.42	gold quality
mucosa of transverse colon	UBERON:0004991	92.35	gold quality
descending thoracic aorta	UBERON:0002345	92.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.29	gold quality
smooth muscle tissue	UBERON:0001135	92.28	gold quality
small intestine	UBERON:0002108	92.18	gold quality
thoracic aorta	UBERON:0001515	92.08	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.84
E-MTAB-6386	no	399.24
E-MTAB-7606	no	169.78

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
AIRE	Repression
AR	Repression
BIRC3	Repression
ETS1	Repression
NR3C1	Repression

Upstream regulators (CollecTRI, top): CUX1, ETS1, NKX2-1, SP1, TP53, TTF1

miRNA regulators (miRDB)

25 targeting DAXX, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-5579-3P	97.00	68.81	1111

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 26.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• interaction with Pax5 resulting in transcriptional activation in B cells (PMID:11799127)
• transcriptional repression modulated by 58-kDa microspherule protein (PMID:11948183)
• Daxx-mediated accumulation of human cytomegalovirus tegument protein pp71 at ND10 facilitates initiation of viral infection at these nuclear domains (PMID:12097584)
• Data show that Daxx associates with proteins critical for transcriptional repression, such as histone deacetylase 2 and Dek, a chromatin-associated protein reported to change the topology of DNA in chromatin in vitro. (PMID:12140263)
• modification by small ubiquitin-related modifier-1 (PMID:12150977)
• Increased apoptosis was observed in DAXX-depleted cells, showing DAXX to be anti-apoptotic. The apoptosis induced by the absence of DAXX was rescued by Bcl-2 overexpression. (PMID:12482920)
• Interaction of Daxx with p53 is highly dependent upon the specific mutation of p53. Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases (PMID:12482984)
• Promyelocytic leukemia protein (PML) functions as a glucocorticoid receptor co-activator by sequestering Daxx to the PML oncogenic domains (PODs) to enhance its transactivation potential. (PMID:12595526)
• These results suggest that ZIPK, in collaboration with Daxx and Par-4, mediates a novel nuclear pathway for apoptosis (PMID:12917339)
• forms complex with ATRX syndrome protein and localizes in promyelocytic leukemia nuclear bodies (PMID:12953102)
• glucose deprivation activates the ASK1-SEK1-JNK1-HIPK1 pathway, relocalizing Daxx from the nucleus to the cytoplasm, where Daxx binds to ASK1, and subsequently leads to ASK1 oligomerization (PMID:12968034)
• Daxx may inhibit Fas and stress-mediated apoptosis by suppressing proapoptotic gene expression outside of PML domains (PMID:14517282)
• binds to the Adenovirus E1B 55-kDa protein and inhibits its augmentation of p53 mediated transcription and thus may contribute to cell transformation. (PMID:14557665)
• In this study, we show that c-FLIP(L) but not c-FLIP(S) physically binds to Daxx through interaction between C-terminal domain of c-FLIP(L) and Fas-binding domain of Daxx, an alternative Fas signaling adaptor. (PMID:14637155)
• the ATRX.Daxx complex is a novel ATP-dependent chromatin-remodeling complex, with ATRX being the core ATPase subunit and Daxx being the targeting subunit (PMID:14990586)
• molecular interactions between Daxx and TSG101 establish an efficient repressive transcription complex in the nucleus (PMID:15033475)
• Tryptophan 621 and serine 667 residues of Daxx regulate its nuclear export during glucose deprivation (PMID:15128734)
• Mutagenesis study suggests that the ability of SPOP to self-associate as well as its ability to bind with Daxx was important for the modulation of Daxx-mediated transcriptional repression. (PMID:15240113)
• Daxx501-625-induced apoptosis is mediated through the ASK1-MEK-JNK/p38-Bim-Bax-dependent caspase pathway (PMID:15258908)
• Results describe the role of Daxx in modulating the apoptotic threshold and identify it as a possible integrating factor that coordinates the response of p53 family members. (PMID:15339933)
• DAXX is a negative regulator of androgen receptor transcriptional activity. (PMID:15572661)
• Daxx suppresses Smad4-mediated transcriptional activity by direct interaction with the sumoylated Smad4 and has a role in regulating transforming growth factor beta signaling (PMID:15637079)
• Daxx interacts with an integrase-viral DNA complex early after infection and may mediate the repression of viral gene expression. (PMID:15795247)
• first evidence that Daxx promotes cell death and JNK activation in physiological conditions (PMID:15861194)
• interaction with human Cytomegalovirus UL82 regulates Cytomegalovirus immediate-early gene expression and viral replication (PMID:15919932)
• Daxx acts as an intermediary messenger of pro-apoptotic signals triggered by oxidative stress (PMID:16088932)
• results indicate that Daxx may serve as a transcriptional regulator of type I IFN-mediated suppression of the IL-6/STAT3 signaling pathway (PMID:16331268)
• SUMO has a biological role in enhancing the cytoplasmonuclear transport of its target protein Daxx (PMID:16475184)
• SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis (PMID:16524876)
• Daxx reduced DNA binding activity of Tcf4 and repressed Tcf4 transcriptional activity. (PMID:16569639)
• the impaired growth phenotype associated with the UL82 (pp71) deletion mutant is abolished when hDaxx knockdown cells are infected, suggesting that pp71 functions to relieve hDaxx-mediated repression during HCMV infection (PMID:16731959)
• Nuclear commponents Daxx and Ras-association domain family 1C (RASSF1C) link DNA damage to stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) activation in HeLa cells. (PMID:16810318)
• Interferon-induced growth suppression of B lymphocytes requires nuclear localization of Daxx through its sumoylation and proper interactions with promyelocytic leukemia protein (PML). (PMID:16818774)
• Daxx in nuclear domain 10 functions at the site of cytomegalovirus genome deposition to repress transcription of incoming viral genomes (PMID:17035242)
• These results provide mechanistic insights into Daxx in SUMO-dependent transcriptional control and subnuclear compartmentalization. (PMID:17081986)
• Upon ischemic stress, nuclear export of Daxx to the cytoplasm was observed in primary myocytes as well as in various cell lines. (PMID:17289031)
• The physical interaction between Daxx and p65 provides a functional framework for the inhibition of p65 acetylation by p300/CBP and subsequent repression of NF-kappaB transcriptional activity. (PMID:17362989)
• Daxx may be an important predictive factor in cellular response to paclitaxel, which emphasizes a critical but unknown function of this protein in mitotic progression, which, when disabled, leads to survival advantages upon paclitaxel treatment. (PMID:17471023)
• Our work demonstrates that, in certain cell types, HCMV must silence its own gene expression to establish quiescence and prevent abortive infection and that the virus usurps a Daxx-mediated cellular intrinsic immune defense mechanism to do so. (PMID:17596307)
• RLKRK at residues 227-231 (NLS1) causes nuclear localization of N-terminal domain & KKSRKEKK at residues 630-637 (NLS2) causes nuclear localization of C-terminal domain. Daxx interacts selectively with importin alpha3 via NLS1 & NLS2. (PMID:17661348)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	daxx	ENSDARG00000000729
mus_musculus	Daxx	ENSMUSG00000002307
rattus_norvegicus	Daxx	ENSRNOG00000000477
drosophila_melanogaster	Daxx	FBGN0031820

Protein

Protein identifiers

Death domain-associated protein 6 — Q9UER7 (reviewed: Q9UER7)

Alternative names: Daxx, ETS1-associated protein 1, Fas death domain-associated protein

All UniProt accessions (6): Q9UER7, A0A024RCS3, A0A994J7Y1, A2AB94, B4E1C1, Q4VX54

UniProt curated annotations — full annotation on UniProt →

Function. Transcription corepressor known to repress transcriptional potential of several sumoylated transcription factors. Down-regulates basal and activated transcription. Its transcription repressor activity is modulated by recruiting it to subnuclear compartments like the nucleolus or PML/POD/ND10 nuclear bodies through interactions with MCSR1 and PML, respectively. Seems to regulate transcription in PML/POD/ND10 nuclear bodies together with PML and may influence TNFRSF6-dependent apoptosis thereby. Inhibits transcriptional activation of PAX3 and ETS1 through direct protein-protein interactions. Modulates PAX5 activity; the function seems to involve CREBBP. Acts as an adapter protein in a MDM2-DAXX-USP7 complex by regulating the RING-finger E3 ligase MDM2 ubiquitination activity. Under non-stress condition, in association with the deubiquitinating USP7, prevents MDM2 self-ubiquitination and enhances the intrinsic E3 ligase activity of MDM2 towards TP53, thereby promoting TP53 ubiquitination and subsequent proteasomal degradation. Upon DNA damage, its association with MDM2 and USP7 is disrupted, resulting in increased MDM2 autoubiquitination and consequently, MDM2 degradation, which leads to TP53 stabilization. Acts as a histone chaperone that facilitates deposition of histone H3.3. Acts as a targeting component of the chromatin remodeling complex ATRX:DAXX which has ATP-dependent DNA translocase activity and catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S-phase and telomeres, and the in vitro remodeling of H3.3-containing nucleosomes. Does not affect the ATPase activity of ATRX but alleviates its transcription repression activity. Upon neuronal activation associates with regulatory elements of selected immediate early genes where it promotes deposition of histone H3.3 which may be linked to transcriptional induction of these genes. Required for the recruitment of histone H3.3:H4 dimers to PML-nuclear bodies (PML-NBs); the process is independent of ATRX and facilitated by ASF1A; PML-NBs are suggested to function as regulatory sites for the incorporation of newly synthesized histone H3.3 into chromatin. In case of overexpression of centromeric histone variant CENPA (as found in various tumors) is involved in its mislocalization to chromosomes; the ectopic localization involves a heterotypic tetramer containing CENPA, and histones H3.3 and H4 and decreases binding of CTCF to chromatin. Proposed to mediate activation of the JNK pathway and apoptosis via MAP3K5 in response to signaling from TNFRSF6 and TGFBR2. Interaction with HSPB1/HSP27 may prevent interaction with TNFRSF6 and MAP3K5 and block DAXX-mediated apoptosis. In contrast, in lymphoid cells JNC activation and TNFRSF6-mediated apoptosis may not involve DAXX. Shows restriction activity towards human cytomegalovirus (HCMV). Plays a role as a positive regulator of the heat shock transcription factor HSF1 activity during the stress protein response.

Subunit / interactions. Homomultimer. Interacts (via C-terminus) with TNFRSF6 (via death domain). Interacts with PAX5, SLC2A4/GLUT4, MAP3K5, TGFBR2, phosphorylated dimeric HSPB1/HSP27, CENPC, ETS1, sumoylated PML, UBE2I, MCRS1 and TP53. Interacts (via N-terminus) with HIPK2 and HIPK3. Interacts with HIPK1, which induces translocation from PML/POD/ND10 nuclear bodies to chromatin and enhances association with HDAC1. Interacts (non-phosphorylated) with PAX3, PAX7, DEK, HDAC1, HDAC2, HDAC3, acetylated histone H4 and histones H2A, H2B, H3, H3.3 and H4. Interacts with SPOP; mediating CUL3-dependent proteasomal degradation. Interacts with CBP; the interaction is dependent the sumoylation of CBP and suppresses CBP transcriptional activity via recruitment of HDAC2 directly in the complex with TP53 and HIPK2. Interacts with AXIN1; the interaction stimulates the interaction of DAXX with TP53, stimulates ‘Ser-46’ phosphorylation of TP53 on and induces cell death on UV irradiation. Interacts with MDM2; the interaction is direct. Interacts with USP7; the interaction is direct and independent of MDM2 and TP53. Part of a complex with DAXX, MDM2 and USP7 under non-stress conditions. Interacts (via N-terminus) with RASSF1 (via C-terminus); the interaction is independent of MDM2 and TP53; RASSF1 isoform A disrupts interactions among MDM2, DAXX and USP7, thus contributing to the efficient activation of TP53 by promoting MDM2 self-ubiquitination in cell-cycle checkpoint control in response to DNA damage. Interacts with ATRX to form the chromatin remodeling complex ATRX:DAXX. Interacts with HSF1 (via homotrimeric form preferentially); this interaction relieves homotrimeric HSF1 from repression of its transcriptional activity by HSP90-dependent multichaperone complex upon heat shock. Interacts with SUMO1P1/SUMO5. (Microbial infection) Interacts with human cytomegalovirus/HHV-5 tegument phosphoprotein pp71 and protein UL123. (Microbial infection) Interacts with Epstein-Barr virus protein BNRF1. (Microbial infection) Interacts with human adenovirus 5 E1B-55K protein; this interaction might alterate the normal interactions of DAXX, PML, and TP53, which may contribute to cell transformation. (Microbial infection) Interacts with Puumala hantavirus nucleoprotein.

Subcellular location. Cytoplasm. Nucleus. Nucleoplasm. PML body. Nucleolus. Chromosome. Centromere Nucleus Nucleus.

Tissue specificity. Ubiquitous.

Post-translational modifications. Sumoylated with SUMO1 on multiple lysine residues. Phosphorylated by HIPK1 upon glucose deprivation. Polyubiquitinated; which is promoted by CUL3 and SPOP and results in proteasomal degradation. Ubiquitinated by MDM2; inducing its degradation. Deubiquitinated by USP7; leading to stabilize it.

Domain organisation. The Sumo interaction motif mediates Sumo binding, and is required both for sumoylation and binding to sumoylated targets.

Induction. Upon mitogenic stimulation by concanavalin-A.

Miscellaneous. Markedly decreased affinity for PML and TP53/p53, unable to repress p53-mediated transcription. Markedly decreased affinity for PML and TP53/p53, unable to repress p53-mediated transcription.

Similarity. Belongs to the DAXX family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9UER7-1	1	yes
Q9UER7-2	2
Q9UER7-3	3
Q9UER7-4	beta
Q9UER7-5	gamma

RefSeq proteins (4): NP_001135441, NP_001135442, NP_001241646, NP_001341 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031333	Daxx_N	Domain
IPR038298	Daxx_N_sf	Homologous_superfamily
IPR046378	DAXX_histone-bd	Domain
IPR046426	DAXX_histone-bd_sf	Homologous_superfamily

Pfam: PF03344, PF20920

UniProt features (98 total): modified residue 17, helix 17, mutagenesis site 15, region of interest 11, compositionally biased region 11, sequence conflict 9, splice variant 6, coiled-coil region 3, cross-link 3, short sequence motif 2, strand 2, chain 1, turn 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
5GRQ	X-RAY DIFFRACTION	1.58
4H9N	X-RAY DIFFRACTION	1.95
4H9Q	X-RAY DIFFRACTION	1.95
4H9O	X-RAY DIFFRACTION	2.05
4H9R	X-RAY DIFFRACTION	2.2
4H9P	X-RAY DIFFRACTION	2.2
5Y18	X-RAY DIFFRACTION	2.2
4H9S	X-RAY DIFFRACTION	2.6
4HGA	X-RAY DIFFRACTION	2.8
5Y6O	X-RAY DIFFRACTION	3.1
5KDM	X-RAY DIFFRACTION	3.5
2KQS	SOLUTION NMR
2KZS	SOLUTION NMR
2KZU	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UER7-F1	64.16	0.40

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (20): 25, 178, 213, 412, 424, 459, 495, 498, 512, 561, 580, 668, 671, 688, 702, 737, 739, 142, 630, 631

Mutagenesis-validated functional residues (15):

Position	Phenotype
206	impairs interaction with histones h3 and h4.
220	abolishes interaction with histones h3 and h4.
222	abolishes interaction with histones h3 and h4.
222	abolishes interaction with histone h3.3.
225	impairs interaction with histones h3 and h4.
229	impairs interaction with histones h3 and h4.
251	abolishes interaction with histones h3 and h4.
317	abolishes interaction with histones h3 and h4.
328	abolishes interaction with histones h3 and h4.
331	abolishes interaction with histones h3 and h4.
630	abolishes sumoylation; when associated with a-631.
631	abolishes sumoylation; when associated with a-630.
668	no translocation to the cytosol upon glucose deprivation.
671	no effect on cytosol translocation. upon glucose deprivation.
733–740	abolishes sumoylation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-6804757	Regulation of TP53 Degradation
R-HSA-9609690	HCMV Early Events
R-HSA-9670095	Inhibition of DNA recombination at telomere
R-HSA-9670613	Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations
R-HSA-9670615	Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations
R-HSA-9920951	Dengue virus modulates apoptosis

MSigDB gene sets: 0 (showing top):

GO Biological Process (21): nucleosome assembly (GO:0006334), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), JNK cascade (GO:0007254), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), regulation of gene expression (GO:0010468), negative regulation of gene expression (GO:0010629), androgen receptor signaling pathway (GO:0030521), regulation of protein ubiquitination (GO:0031396), cellular response to heat (GO:0034605), cellular response to unfolded protein (GO:0034620), neuron intrinsic apoptotic signaling pathway in response to oxidative stress (GO:0036480), regulation of apoptotic process (GO:0042981), negative regulation of DNA-templated transcription (GO:0045892), cellular response to cadmium ion (GO:0071276), cellular response to copper ion (GO:0071280), cellular response to diamide (GO:0072738), cellular response to sodium arsenite (GO:1903936), chromatin organization (GO:0006325), apoptotic process (GO:0006915), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (15): p53 binding (GO:0002039), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), protein kinase activator activity (GO:0030295), heat shock protein binding (GO:0031072), ubiquitin protein ligase binding (GO:0031625), histone binding (GO:0042393), protein homodimerization activity (GO:0042803), nuclear androgen receptor binding (GO:0050681), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), transcription regulator inhibitor activity (GO:0140416), molecular condensate scaffold activity (GO:0140693), protein binding (GO:0005515)

GO Cellular Component (9): chromosome, centromeric region (GO:0000775), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), nuclear body (GO:0016604), PML body (GO:0016605), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Defective Inhibition of DNA Recombination at Telomere	2
SUMO E3 ligases SUMOylate target proteins	1
Regulation of TP53 Expression and Degradation	1
HCMV Infection	1
Telomere Maintenance	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
regulation of gene expression	3
cellular anatomical structure	3
intracellular membraneless organelle	3
chromatin organization	2
DNA-templated transcription	2
gene expression	2
cellular response to metal ion	2
transcription coregulator activity	2
nuclear lumen	2
nucleosome organization	1
protein-DNA complex assembly	1
regulation of RNA biosynthetic process	1
MAPK cascade	1
extrinsic apoptotic signaling pathway	1
regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
nuclear receptor-mediated steroid hormone signaling pathway	1
protein ubiquitination	1
regulation of protein modification by small protein conjugation or removal	1
response to heat	1
cellular response to stress	1
response to unfolded protein	1
cellular response to topologically incorrect protein	1
intrinsic apoptotic signaling pathway in response to oxidative stress	1
neuron apoptotic process	1
apoptotic process	1
regulation of programmed cell death	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
response to cadmium ion	1
response to copper ion	1
response to diamide	1
cellular response to nitrogen compound	1
cellular response to arsenic-containing substance	1
cellular response to salt	1
response to sodium arsenite	1
cellular component organization	1
programmed cell death	1
apoptotic signaling pathway	1

Protein interactions and networks

STRING

3067 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DAXX	ATRX	P46100	998
DAXX	SP100	P23497	996
DAXX	USP7	Q93009	994
DAXX	MAP3K5	Q99683	993
DAXX	PML	P29590	975
DAXX	MDM2	Q00987	953
DAXX	SUMO1	P55856	953
DAXX	TP53	P04637	952
DAXX	H3-3A	P06351	948
DAXX	FAS	P25445	941
DAXX	SMAD4	Q13485	915
DAXX	SPOP	O43791	876
DAXX	SLC2A4	P14672	841
DAXX	FADD	Q13158	836
DAXX	HSPB1	P04792	831

IntAct

467 interactions, top by confidence:

A	B	Type	Score
DAXX	MDM2	psi-mi:“MI:0915”(physical association)	0.890
MDM2	DAXX	psi-mi:“MI:0403”(colocalization)	0.890
DAXX	MDM2	psi-mi:“MI:0914”(association)	0.890
TP53	DAXX	psi-mi:“MI:0407”(direct interaction)	0.880
DAXX	TP53	psi-mi:“MI:0407”(direct interaction)	0.880
DAXX	TP53	psi-mi:“MI:0915”(physical association)	0.880
DAXX	TP53	psi-mi:“MI:0914”(association)	0.880
TP53	DAXX	psi-mi:“MI:0915”(physical association)	0.880
DAXX	TP53	psi-mi:“MI:0403”(colocalization)	0.880
H3-3A	DAXX	psi-mi:“MI:0915”(physical association)	0.850
DAXX	MAP3K5	psi-mi:“MI:0915”(physical association)	0.810
DAXX	MAP3K5	psi-mi:“MI:0403”(colocalization)	0.810
GOLGA2	DAXX	psi-mi:“MI:0915”(physical association)	0.790
DAXX	GOLGA2	psi-mi:“MI:0915”(physical association)	0.790
DAXX	PML	psi-mi:“MI:0403”(colocalization)	0.790
DAXX	PML	psi-mi:“MI:0914”(association)	0.790
MCRS1	DAXX	psi-mi:“MI:0915”(physical association)	0.790
SUMO1	DAXX	psi-mi:“MI:0915”(physical association)	0.780
DAXX	SUMO1	psi-mi:“MI:0915”(physical association)	0.780
DAXX	NECAB2	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (771): DAXX (Affinity Capture-Western), UBE2I (Reconstituted Complex), DAXX (Biochemical Activity), GOLGA2 (Two-hybrid), NECAB2 (Two-hybrid), CDCA7L (Two-hybrid), PBXIP1 (Two-hybrid), CARD9 (Two-hybrid), SSX2IP (Two-hybrid), FAM9B (Two-hybrid), DAXX (Reconstituted Complex), DAXX (Two-hybrid), DAXX (Affinity Capture-Western), DAXX (Two-hybrid), DAXX (Biochemical Activity)

ESM2 similar proteins: A0FKI7, A1L1M4, A5X7A0, A7XYJ6, A8MW92, E1BE02, F8VPQ2, O18805, O35613, O94885, P59598, P59808, Q0VGB7, Q13029, Q28IG6, Q4V9H5, Q5M7D6, Q5R9U6, Q5RJ80, Q5TJE1, Q5XG73, Q5ZHQ6, Q5ZM88, Q5ZMU6, Q63755, Q640U0, Q641E3, Q6DCQ0, Q6I6G8, Q6KAQ7, Q6P964, Q6ZQ03, Q76L83, Q76LL6, Q76N89, Q7TT18, Q8BLG0, Q8BZ32, Q8C9B9, Q8CCJ9

Diamond homologs: O18805, O35613, Q5TJE1, Q8VIB2, Q9UER7, Q9VMD0

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
DAXX	up-regulates	TGFBR2	binding
MAP3K5	“up-regulates quantity by stabilization”	DAXX	phosphorylation
CSNK2A1	up-regulates	DAXX	phosphorylation
MAP3K5	up-regulates	DAXX	phosphorylation
ATM	down-regulates	DAXX	phosphorylation
DAXX	up-regulates	MDM2	binding
DAXX	“down-regulates activity”	AIRE	binding
DAXX	down-regulates	Immortality
HIPK1	“down-regulates activity”	DAXX	phosphorylation
SPOP	“down-regulates quantity”	DAXX	ubiquitination
DAXX	down-regulates	FAS	binding
DAXX	up-regulates	MAP3K5	binding
FAS	up-regulates	DAXX

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 76 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of transcription factors	5	71.4×	3e-06
SUMO E3 ligases SUMOylate target proteins	5	22.3×	4e-04
SUMOylation	5	20.4×	4e-04
SUMOylation of chromatin organization proteins	5	19.8×	4e-04
SUMOylation of DNA damage response and repair proteins	5	18.3×	4e-04
NuRD complex assembly	5	17.6×	5e-04
Oxidative Stress Induced Senescence	7	15.9×	5e-05
PIP3 activates AKT signaling	5	8.3×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein sumoylation	6	30.4×	3e-05
protein stabilization	7	7.3×	7e-03
positive regulation of apoptotic process	7	6.2×	1e-02
negative regulation of apoptotic process	9	4.9×	8e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — ACC, PANCREAS, PANET.

Clinical variants and AI predictions

ClinVar

100 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	17
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1195 predictions. Top by Δscore:

Variant	Effect	Δscore
6:33319644:T:TA	donor_gain	1.0000
6:33319850:TTTAC:T	acceptor_gain	1.0000
6:33319851:TTAC:T	acceptor_gain	1.0000
6:33319852:TACC:T	acceptor_loss	1.0000
6:33319854:CCT:C	acceptor_loss	1.0000
6:33319855:C:CA	acceptor_loss	1.0000
6:33319855:C:CC	acceptor_gain	1.0000
6:33319856:T:A	acceptor_loss	1.0000
6:33320006:CATA:C	donor_loss	1.0000
6:33320007:ATAC:A	donor_loss	1.0000
6:33320009:A:AC	donor_gain	1.0000
6:33320010:C:CC	donor_gain	1.0000
6:33320010:CCTG:C	donor_gain	1.0000
6:33320025:T:TA	donor_gain	1.0000
6:33320320:C:CA	donor_gain	1.0000
6:33320589:CGC:C	acceptor_gain	1.0000
6:33320590:GCCT:G	acceptor_loss	1.0000
6:33320592:C:CC	acceptor_gain	1.0000
6:33320593:T:G	acceptor_loss	1.0000
6:33320750:T:C	donor_gain	1.0000
6:33321568:C:CC	acceptor_gain	1.0000
6:33321713:GCTCA:G	donor_loss	1.0000
6:33321714:CTCAC:C	donor_loss	1.0000
6:33321715:TCA:T	donor_loss	1.0000
6:33321716:CACCT:C	donor_loss	1.0000
6:33321717:A:AC	donor_gain	1.0000
6:33321717:ACC:A	donor_loss	1.0000
6:33321718:C:CC	donor_gain	1.0000
6:33321718:CCT:C	donor_gain	1.0000
6:33321942:C:CT	acceptor_gain	1.0000

AlphaMissense

4800 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:33320824:G:C	F317L	0.999
6:33320824:G:T	F317L	0.999
6:33320825:A:G	F317S	0.999
6:33320826:A:G	F317L	0.999
6:33320837:G:T	A313D	0.999
6:33320971:G:C	N268K	0.999
6:33320971:G:T	N268K	0.999
6:33320549:A:G	L361P	0.998
6:33320792:C:G	R328P	0.998
6:33320793:G:T	R328S	0.998
6:33320795:C:G	R327P	0.998
6:33320813:C:T	G321D	0.998
6:33320975:A:T	V267D	0.998
6:33320985:A:C	Y264D	0.998
6:33321000:A:C	Y259D	0.998
6:33321056:C:T	C240Y	0.998
6:33321080:A:G	L232P	0.998
6:33320780:A:G	L332P	0.997
6:33320804:A:G	L324S	0.997
6:33320814:C:G	G321R	0.997
6:33320838:C:G	A313P	0.997
6:33320909:A:T	V289E	0.997
6:33321050:A:G	L242P	0.997
6:33321059:A:G	L239P	0.997
6:33321161:A:G	L205P	0.997
6:33320829:C:G	A316P	0.996
6:33320951:A:T	I275N	0.996
6:33321055:A:C	C240W	0.996
6:33321067:A:C	F236L	0.996
6:33321067:A:T	F236L	0.996

dbSNP variants (sampled 300 via entrez): RS1001183533 (6:33321782 T>C), RS1002049894 (6:33323287 G>A,C,T), RS1002186003 (6:33323136 C>G), RS1003238652 (6:33324914 GA>G,GAA,GAAAAAAAAA,GAAAAAAAAAA,GAAAAAAAAAAAAA,GAAAAAAAAAAAAAAA,GAAAAAAAAAAAAAAAA,GAAAAAAAAAAAAAAAAAAA), RS1003670609 (6:33318089 GC>G), RS1005514905 (6:33324155 A>G), RS1006445996 (6:33319369 CTTG>C), RS1007233410 (6:33318444 A>G,T), RS1008495663 (6:33323704 C>T), RS1008675216 (6:33318917 T>A,G), RS1008707649 (6:33318470 G>A), RS1009809061 (6:33323320 A>G,T), RS1010089014 (6:33319899 G>A), RS1010652170 (6:33318365 G>A,C), RS1011617239 (6:33323674 C>T)

Disease associations

OMIM: gene MIM:603186 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004521_251	Autism spectrum disorder or schizophrenia	6.000000e-12
GCST004521_287	Autism spectrum disorder or schizophrenia	5.000000e-08
GCST004748_120	Lung cancer	2.000000e-06
GCST004749_13	Lung cancer in ever smokers	8.000000e-06
GCST006396_8	Disrupted circadian rhythm (low relative amplitude of rest-activity cycles)	2.000000e-06
GCST010988_358	Adult body size	6.000000e-14

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724773 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.80	IC50	1600	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178854: Inhibition of DAXX (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	1.6000	uM

CTD chemical–gene interactions

70 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation, affects methylation	3
sodium arsenite	decreases expression	2
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Resveratrol	affects binding, decreases reaction, increases reaction, decreases expression	2
Arsenic Trioxide	decreases reaction, decreases expression, affects binding, affects reaction	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Smoke	decreases expression, increases abundance	2
Valproic Acid	decreases expression, increases expression, increases methylation	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases methylation, affects cotreatment	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
oxybenzone	increases methylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, affects methylation, increases methylation	1
trichostatin A	affects expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
coumarin	affects phosphorylation	1
aluminum sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
2-palmitoylglycerol	increases expression	1
fenpyroximate	decreases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697584	Binding	Inhibition of DAXX (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

18 cell lines: 14 cancer cell line, 3 spontaneously immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_2909	G-292 clone A141B1	Cancer cell line	Female
CVCL_B1PT	Abcam HeLa DAXX KO	Cancer cell line	Female
CVCL_B8EI	Abcam HCT 116 DAXX KO	Cancer cell line	Male
CVCL_B8UL	Abcam MCF-7 DAXX KO	Cancer cell line	Female
CVCL_B9GR	Abcam A-549 DAXX KO	Cancer cell line	Male
CVCL_C0ZU	MCF10A_DAXX_703_SC1	Spontaneously immortalized cell line	Female
CVCL_C0ZV	MCF10A_DAXX_704	Spontaneously immortalized cell line	Female
CVCL_C0ZW	MCF10A_DAXX_715	Spontaneously immortalized cell line	Female
CVCL_C4N5	NT-18LM	Cancer cell line	Male
CVCL_C4N6	NT-18P	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.