Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX6O7PL)

• DOT Name: Death domain-associated protein 6 (DAXX)
• Synonyms: Daxx; hDaxx; ETS1-associated protein 1; EAP1; Fas death domain-associated protein
• Gene Name: DAXX
• Related Disease:
  Acute myelogenous leukaemia
  Adrenocortical carcinoma
  Adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Alpha thalassemia
  Alpha thalassemia-X-linked intellectual disability syndrome
  Alzheimer disease
  B-cell lymphoma
  Bone osteosarcoma
  Carcinoma
  Colorectal carcinoma
  Coronary microvascular disease
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  Huntington disease
  Leukemia
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Multiple endocrine neoplasia type 1
  Neuroendocrine neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic neuroendocrine tumor
  Pancreatic tumour
  Promyelocytic leukaemia
  Retinoblastoma
  Sarcoma
  Schizophrenia
  Small-cell lung cancer
  Triple negative breast cancer
  Gastric cancer
  Melanoma
  Progressive multifocal leukoencephalopathy
  Stomach cancer
  Multiple sclerosis
  Pancreatic ductal carcinoma
  Neuroblastoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Rheumatoid arthritis
  Type-1 diabetes
• UniProt ID: DAXX_HUMAN
• PDB ID: 2KQS; 2KZS; 2KZU; 4H9N; 4H9O; 4H9P; 4H9Q; 4H9R; 4H9S; 4HGA; 5GRQ; 5KDM; 5Y18; 5Y6O
• Pfam ID: PF03344 ; PF20920
• Sequence:
  MATANSIIVLDDDDEDEAAAQPGPSHPLPNAASPGAEAPSSSEPHGARGSSSSGGKKCYK
  LENEKLFEEFLELCKMQTADHPEVVPFLYNRQQRAHSLFLASAEFCNILSRVLSRARSRP
  AKLYVYINELCTVLKAHSAKKKLNLAPAATTSNEPSGNNPPTHLSLDPTNAENTASQSPR
  TRGSRRQIQRLEQLLALYVAEIRRLQEKELDLSELDDPDSAYLQEARLKRKLIRLFGRLC
  ELKDCSSLTGRVIEQRIPYRGTRYPEVNRRIERLINKPGPDTFPDYGDVLRAVEKAAARH
  SLGLPRQQLQLMAQDAFRDVGIRLQERRHLDLIYNFGCHLTDDYRPGVDPALSDPVLARR
  LRENRSLAMSRLDEVISKYAMLQDKSEEGERKKRRARLQGTSSHSADTPEASLDSGEGPS
  GMASQGCPSASRAETDDEDDEESDEEEEEEEEEEEEEATDSEEEEDLEQMQEGQEDDEEE
  DEEEEAAAGKDGDKSPMSSLQISNEKNLEPGKQISRSSGEQQNKGRIVSPSLLSEEPLAP
  SSIDAESNGEQPEELTLEEESPVSQLFELEIEALPLDTPSSVETDISSSRKQSEEPFTTV
  LENGAGMVSSTSFNGGVSPHNWGDSGPPCKKSRKEKKQTGSGPLGNSYVERQRSVHEKNG
  KKICTLPSPPSPLASLAPVADSSTRVDSPSHGLVTSSLCIPSPARLSQTPHSQPPRPGTC
  KTSVATQCDPEEIIVLSDSD
• 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.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Apoptosis (hsa04210)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  Regulation of TP53 Degradation (R-HSA-6804757)
  HCMV Early Events (R-HSA-9609690)
  Inhibition of DNA recombination at telomere (R-HSA-9670095)
  Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations (R-HSA-9670613)
  Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations (R-HSA-9670615)
  SUMOylation of transcription cofactors (R-HSA-3899300)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Adrenocortical carcinoma	DISZF4HX	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[5]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[6]
Alpha thalassemia-X-linked intellectual disability syndrome	DISV7OEV	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[7]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[8]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[9]
Carcinoma	DISH9F1N	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Coronary microvascular disease	DISTU5VE	Strong	Altered Expression	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[13]
Huntington disease	DISQPLA4	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Altered Expression	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[16]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Genetic Variation	[16]
Neuroendocrine neoplasm	DISNPLOO	Strong	Biomarker	[17]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[9]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Pancreatic neuroendocrine tumor	DISDMPU0	Strong	Biomarker	[18]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[19]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[20]
Retinoblastoma	DISVPNPB	Strong	Genetic Variation	[21]
Sarcoma	DISZDG3U	Strong	Biomarker	[22]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[23]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[3]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[24]
Gastric cancer	DISXGOUK	moderate	Biomarker	[25]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[26]
Progressive multifocal leukoencephalopathy	DISX02WS	moderate	Biomarker	[27]
Stomach cancer	DISKIJSX	moderate	Biomarker	[25]
Multiple sclerosis	DISB2WZI	Disputed	Altered Expression	[28]
Pancreatic ductal carcinoma	DIS26F9Q	Disputed	Genetic Variation	[29]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[30]
Prostate cancer	DISF190Y	Limited	Biomarker	[31]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[31]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[31]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[32]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[33]

10 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Death domain-associated protein 6 (DAXX).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Death domain-associated protein 6 (DAXX).	[39]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Death domain-associated protein 6 (DAXX).	[40]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Death domain-associated protein 6 (DAXX).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Death domain-associated protein 6 (DAXX).	[48]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Death domain-associated protein 6 (DAXX).	[50]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Death domain-associated protein 6 (DAXX).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Death domain-associated protein 6 (DAXX).	[42]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Death domain-associated protein 6 (DAXX).	[40]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the methylation of Death domain-associated protein 6 (DAXX).	[54]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Death domain-associated protein 6 (DAXX).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Death domain-associated protein 6 (DAXX).	[36]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Death domain-associated protein 6 (DAXX).	[37]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Death domain-associated protein 6 (DAXX).	[38]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Death domain-associated protein 6 (DAXX).	[41]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Death domain-associated protein 6 (DAXX).	[43]
Aluminium	DM6ECN9	Approved	Aluminium increases the expression of Death domain-associated protein 6 (DAXX).	[44]
Bendamustine hydrochloride	DMFH15Z	Approved	Bendamustine hydrochloride decreases the expression of Death domain-associated protein 6 (DAXX).	[45]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Death domain-associated protein 6 (DAXX).	[46]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Death domain-associated protein 6 (DAXX).	[47]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Death domain-associated protein 6 (DAXX).	[49]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Death domain-associated protein 6 (DAXX).	[51]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Death domain-associated protein 6 (DAXX).	[52]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Death domain-associated protein 6 (DAXX).	[46]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose affects the localization of Death domain-associated protein 6 (DAXX).	[53]

References

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