Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT77RSQW)

• DOT Name: Transcriptional regulator ATRX (ATRX)
• Synonyms: EC 3.6.4.12; ATP-dependent helicase ATRX; X-linked helicase II; X-linked nuclear protein; XNP; Znf-HX
• Gene Name: ATRX
• Related Disease:
  Alpha thalassemia-X-linked intellectual disability syndrome
  ATR-X-related syndrome
  Adenocarcinoma
  Advanced cancer
  Anaplastic astrocytoma
  Astrocytoma
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Childhood myelodysplastic syndrome
  Colorectal carcinoma
  Cryptorchidism
  Ependymoma
  Glioblastoma multiforme
  Glioma
  Hemoglobin H disease
  Hepatocellular carcinoma
  Herpes simplex infection
  Intellectual disability
  Leukemia
  Malignant soft tissue neoplasm
  Metastatic malignant neoplasm
  Neuroblastoma
  Neuroendocrine neoplasm
  Neurofibromatosis type 1
  Pancreatic neuroendocrine tumor
  Pancreatic tumour
  Paraganglioma
  Progressive multifocal leukoencephalopathy
  Promyelocytic leukaemia
  Sarcoma
  X-linked intellectual disability
  Autism
  Carcinoma
  Intellectual disability-hypotonic facies syndrome, X-linked, 1
  Movement disorder
  Adult glioblastoma
  Isolated congenital microcephaly
  Alpha thalassemia
  Malignant glioma
  Mixed glioma
  Myelodysplastic syndrome
  Penile disorder
• UniProt ID: ATRX_HUMAN
• PDB ID: 2JM1; 2LBM; 2LD1; 3QL9; 3QLA; 3QLC; 3QLN; 4W5A; 5GRQ; 5Y18; 5Y6O; 6G0O
• EC Number: 3.6.4.12
• Pfam ID: PF17981 ; PF00271 ; PF00176
• Sequence:
  MTAEPMSESKLNTLVQKLHDFLAHSSEESEETSSPPRLAMNQNTDKISGSGSNSDMMENS
  KEEGTSSSEKSKSSGSSRSKRKPSIVTKYVESDDEKPLDDETVNEDASNENSENDITMQS
  LPKGTVIVQPEPVLNEDKDDFKGPEFRSRSKMKTENLKKRGEDGLHGIVSCTACGQQVNH
  FQKDSIYRHPSLQVLICKNCFKYYMSDDISRDSDGMDEQCRWCAEGGNLICCDFCHNAFC
  KKCILRNLGRKELSTIMDENNQWYCYICHPEPLLDLVTACNSVFENLEQLLQQNKKKIKV
  DSEKSNKVYEHTSRFSPKKTSSNCNGEEKKLDDSCSGSVTYSYSALIVPKEMIKKAKKLI
  ETTANMNSSYVKFLKQATDNSEISSATKLRQLKAFKSVLADIKKAHLALEEDLNSEFRAM
  DAVNKEKNTKEHKVIDAKFETKARKGEKPCALEKKDISKSEAKLSRKQVDSEHMHQNVPT
  EEQRTNKSTGGEHKKSDRKEEPQYEPANTSEDLDMDIVSVPSSVPEDIFENLETAMEVQS
  SVDHQGDGSSGTEQEVESSSVKLNISSKDNRGGIKSKTTAKVTKELYVKLTPVSLSNSPI
  KGADCQEVPQDKDGYKSCGLNPKLEKCGLGQENSDNEHLVENEVSLLLEESDLRRSPRVK
  TTPLRRPTETNPVTSNSDEECNETVKEKQKLSVPVRKKDKRNSSDSAIDNPKPNKLPKSK
  QSETVDQNSDSDEMLAILKEVSRMSHSSSSDTDINEIHTNHKTLYDLKTQAGKDDKGKRK
  RKSSTSGSDFDTKKGKSAKSSIISKKKRQTQSESSNYDSELEKEIKSMSKIGAARTTKKR
  IPNTKDFDSSEDEKHSKKGMDNQGHKNLKTSQEGSSDDAERKQERETFSSAEGTVDKDTT
  IMELRDRLPKKQQASASTDGVDKLSGKEESFTSLEVRKVAETKEKSKHLKTKTCKKVQDG
  LSDIAEKFLKKDQSDETSEDDKKQSKKGTEEKKKPSDFKKKVIKMEQQYESSSDGTEKLP
  EREEICHFPKGIKQIKNGTTDGEKKSKKIRDKTSKKKDELSDYAEKSTGKGDSCDSSEDK
  KSKNGAYGREKKRCKLLGKSSRKRQDCSSSDTEKYSMKEDGCNSSDKRLKRIELRERRNL
  SSKRNTKEIQSGSSSSDAEESSEDNKKKKQRTSSKKKAVIVKEKKRNSLRTSTKRKQADI
  TSSSSSDIEDDDQNSIGEGSSDEQKIKPVTENLVLSSHTGFCQSSGDEALSKSVPVTVDD
  DDDDNDPENRIAKKMLLEEIKANLSSDEDGSSDDEPEEGKKRTGKQNEENPGDEEAKNQV
  NSESDSDSEESKKPRYRHRLLRHKLTVSDGESGEEKKTKPKEHKEVKGRNRRKVSSEDSE
  DSDFQESGVSEEVSESEDEQRPRTRSAKKAELEENQRSYKQKKKRRRIKVQEDSSSENKS
  NSEEEEEEKEEEEEEEEEEEEEEEDENDDSKSPGKGRKKIRKILKDDKLRTETQNALKEE
  EERRKRIAEREREREKLREVIEIEDASPTKCPITTKLVLDEDEETKEPLVQVHRNMVIKL
  KPHQVDGVQFMWDCCCESVKKTKKSPGSGCILAHCMGLGKTLQVVSFLHTVLLCDKLDFS
  TALVVCPLNTALNWMNEFEKWQEGLKDDEKLEVSELATVKRPQERSYMLQRWQEDGGVMI
  IGYEMYRNLAQGRNVKSRKLKEIFNKALVDPGPDFVVCDEGHILKNEASAVSKAMNSIRS
  RRRIILTGTPLQNNLIEYHCMVNFIKENLLGSIKEFRNRFINPIQNGQCADSTMVDVRVM
  KKRAHILYEMLAGCVQRKDYTALTKFLPPKHEYVLAVRMTSIQCKLYQYYLDHLTGVGNN
  SEGGRGKAGAKLFQDFQMLSRIWTHPWCLQLDYISKENKGYFDEDSMDEFIASDSDETSM
  SLSSDDYTKKKKKGKKGKKDSSSSGSGSDNDVEVIKVWNSRSRGGGEGNVDETGNNPSVS
  LKLEESKATSSSNPSSPAPDWYKDFVTDADAEVLEHSGKMVLLFEILRMAEEIGDKVLVF
  SQSLISLDLIEDFLELASREKTEDKDKPLIYKGEGKWLRNIDYYRLDGSTTAQSRKKWAE
  EFNDETNVRGRLFIISTKAGSLGINLVAANRVIIFDASWNPSYDIQSIFRVYRFGQTKPV
  YVYRFLAQGTMEDKIYDRQVTKQSLSFRVVDQQQVERHFTMNELTELYTFEPDLLDDPNS
  EKKKKRDTPMLPKDTILAELLQIHKEHIVGYHEHDSLLDHKEEEELTEEERKAAWAEYEA
  EKKGLTMRFNIPTGTNLPPVSFNSQTPYIPFNLGALSAMSNQQLEDLINQGREKVVEATN
  SVTAVRIQPLEDIISAVWKENMNLSEAQVQALALSRQASQELDVKRREAIYNDVLTKQQM
  LISCVQRILMNRRLQQQYNQQQQQQMTYQQATLGHLMMPKPPNLIMNPSNYQQIDMRGMY
  QPVAGGMQPPPLQRAPPPMRSKNPGPSQGKSM
• Function: Involved in transcriptional regulation and chromatin remodeling. Facilitates DNA replication in multiple cellular environments and is required for efficient replication of a subset of genomic loci. Binds to DNA tandem repeat sequences in both telomeres and euchromatin and in vitro binds DNA quadruplex structures. May help stabilizing G-rich regions into regular chromatin structures by remodeling G4 DNA and incorporating H3.3-containing nucleosomes. Catalytic 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. Its heterochromatin targeting is proposed to involve a combinatorial readout of histone H3 modifications (specifically methylation states of H3K9 and H3K4) and association with CBX5. Involved in maintaining telomere structural integrity in embryonic stem cells which probably implies recruitment of CBX5 to telomeres. Reports on the involvement in transcriptional regulation of telomeric repeat-containing RNA (TERRA) are conflicting; according to a report, it is not sufficient to decrease chromatin condensation at telomeres nor to increase expression of telomeric RNA in fibroblasts. May be involved in telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines. Acts as a negative regulator of chromatin incorporation of transcriptionally repressive histone MACROH2A1, particularily at telomeres and the alpha-globin cluster in erythroleukemic cells. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, required for the chromatin occupancy of SMC1 and CTCTF within the H19 imprinting control region (ICR) and involved in esatblishment of histone tails modifications in the ICR. May be involved in brain development and facial morphogenesis. Binds to zinc-finger coding genes with atypical chromatin signatures and regulates its H3K9me3 levels. Forms a complex with ZNF274, TRIM28 and SETDB1 to facilitate the deposition and maintenance of H3K9me3 at the 3' exons of zinc-finger genes.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  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)
  Inhibition of DNA recombination at telomere (R-HSA-9670095)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alpha thalassemia-X-linked intellectual disability syndrome	DISV7OEV	Definitive	X-linked	[1]
ATR-X-related syndrome	DISBS7R7	Definitive	X-linked	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Anaplastic astrocytoma	DISSBE0K	Strong	Genetic Variation	[5]
Astrocytoma	DISL3V18	Strong	Genetic Variation	[6]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[7]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[8]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[8]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Cryptorchidism	DISYUD2P	Strong	Biomarker	[11]
Ependymoma	DISUMRNZ	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[13]
Glioma	DIS5RPEH	Strong	Genetic Variation	[4]
Hemoglobin H disease	DISHFWO5	Strong	Genetic Variation	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[14]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[15]
Leukemia	DISNAKFL	Strong	Genetic Variation	[16]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[18]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[19]
Neuroendocrine neoplasm	DISNPLOO	Strong	Biomarker	[20]
Neurofibromatosis type 1	DIS53JH9	Strong	Genetic Variation	[6]
Pancreatic neuroendocrine tumor	DISDMPU0	Strong	Genetic Variation	[21]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[22]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[23]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[24]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[14]
Sarcoma	DISZDG3U	Strong	Biomarker	[17]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[25]
Autism	DISV4V1Z	moderate	Altered Expression	[26]
Carcinoma	DISH9F1N	moderate	Altered Expression	[27]
Intellectual disability-hypotonic facies syndrome, X-linked, 1	DISC5AVJ	Moderate	X-linked	[1]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[28]
Adult glioblastoma	DISVP4LU	Disputed	Genetic Variation	[29]
Isolated congenital microcephaly	DISUXHZ6	Disputed	Altered Expression	[15]
Alpha thalassemia	DIS5XGK0	Limited	Genetic Variation	[30]
Malignant glioma	DISFXKOV	Limited	Biomarker	[31]
Mixed glioma	DIS64UY3	Limited	Biomarker	[32]
Myelodysplastic syndrome	DISYHNUI	Limited	Genetic Variation	[9]
Penile disorder	DISI0KH5	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Transcriptional regulator ATRX (ATRX) affects the response to substance of Mitomycin.	[60]
Josamycin	DMKJ8LB	Approved	Transcriptional regulator ATRX (ATRX) affects the response to substance of Josamycin.	[61]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transcriptional regulator ATRX (ATRX).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcriptional regulator ATRX (ATRX).	[34]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcriptional regulator ATRX (ATRX).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcriptional regulator ATRX (ATRX).	[36]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcriptional regulator ATRX (ATRX).	[37]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcriptional regulator ATRX (ATRX).	[38]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcriptional regulator ATRX (ATRX).	[39]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Transcriptional regulator ATRX (ATRX).	[40]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcriptional regulator ATRX (ATRX).	[41]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transcriptional regulator ATRX (ATRX).	[42]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transcriptional regulator ATRX (ATRX).	[43]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Transcriptional regulator ATRX (ATRX).	[44]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Transcriptional regulator ATRX (ATRX).	[45]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate increases the expression of Transcriptional regulator ATRX (ATRX).	[46]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Transcriptional regulator ATRX (ATRX).	[47]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Transcriptional regulator ATRX (ATRX).	[48]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Transcriptional regulator ATRX (ATRX).	[49]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Transcriptional regulator ATRX (ATRX).	[50]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Transcriptional regulator ATRX (ATRX).	[35]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transcriptional regulator ATRX (ATRX).	[43]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transcriptional regulator ATRX (ATRX).	[53]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Transcriptional regulator ATRX (ATRX).	[55]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Transcriptional regulator ATRX (ATRX).	[56]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcriptional regulator ATRX (ATRX).	[57]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcriptional regulator ATRX (ATRX).	[58]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Transcriptional regulator ATRX (ATRX).	[59]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcriptional regulator ATRX (ATRX).	[51]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Transcriptional regulator ATRX (ATRX).	[52]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transcriptional regulator ATRX (ATRX).	[54]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Transcriptional regulator ATRX (ATRX).	[54]

References

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