Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT78O9LF)

• DOT Name: ATR-interacting protein (ATRIP)
• Synonyms: ATM and Rad3-related-interacting protein
• Gene Name: ATRIP
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Aicardi-Goutieres syndrome
  Aicardi-Goutieres syndrome 1
  Ataxia-telangiectasia
  Chilblain lupus 1
  Mantle cell lymphoma
  Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Seckel syndrome
• UniProt ID: ATRIP_HUMAN
• PDB ID: 4IGK; 4NB3; 5YZ0; 7XV4
• Sequence:
  MAGTSAPGSKRRSEPPAPRPGPPPGTGHPPSKRARGFSAAAAPDPDDPFGAHGDFTADDL
  EELDTLASQALSQCPAAARDVSSDHKVHRLLDGMSKNPSGKNRETVPIKDNFELEVLQAQ
  YKELKEKMKVMEEEVLIKNGEIKILRDSLHQTESVLEEQRRSHFLLEQEKTQALSDKEKE
  FSKKLQSLQSELQFKDAEMNELRTKLQTSERANKLAAPSVSHVSPRKNPSVVIKPEACSP
  QFGKTSFPTKESFSANMSLPHPCQTESGYKPLVGREDSKPHSLRGDSIKQEEAQKSFVDS
  WRQRSNTQGSILINLLLKQPLIPGSSLSLCHLLSSSSESPAGTPLQPPGFGSTLAGMSGL
  RTTGSYDGSFSLSALREAQNLAFTGLNLVARNECSRDGDPAEGGRRAFPLCQLPGAVHFL
  PLVQFFIGLHCQALQDLAAAKRSGAPGDSPTHSSCVSSGVETNPEDSVCILEGFSVTALS
  ILQHLVCHSGAVVSLLLSGVGADSAAGEGNRSLVHRLSDGDMTSALRGVADDQGQHPLLK
  MLLHLLAFSSAATGHLQASVLTQCLKVLVKLAENTSCDFLPRFQCVFQVLPKCLSPETPL
  PSVLLAVELLSLLADHDQLAPQLCSHSEGCLLLLLYMYITSRPDRVALETQWLQLEQEVV
  WLLAKLGVQSPLPPVTGSNCQCNVEVVRALTVMLHRQWLTVRRAGGPPRTDQQRRTVRCL
  RDTVLLLHGLSQKDKLFMMHCVEVLHQFDQVMPGVSMLIRGLPDVTDCEEAALDDLCAAE
  TDVEDPEVECG
• Function: Required for checkpoint signaling after DNA damage. Required for ATR expression, possibly by stabilizing the protein.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Fanconi Anemia Pathway (R-HSA-6783310)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Activation of ATR in response to replication stress (R-HSA-176187)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Genetic Variation	[3]
Aicardi-Goutieres syndrome 1	DISPAXC2	Strong	CausalMutation	[4]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[5]
Chilblain lupus 1	DISEBS1O	Strong	CausalMutation	[4]
Mantle cell lymphoma	DISFREOV	Strong	Posttranslational Modification	[6]
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	DISI621C	Strong	CausalMutation	[4]
Epithelial ovarian cancer	DIS56MH2	moderate	Biomarker	[7]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	moderate	Biomarker	[7]
Seckel syndrome	DISEVUBA	Supportive	Autosomal recessive	[8]

4 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 ATR-interacting protein (ATRIP).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ATR-interacting protein (ATRIP).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATR-interacting protein (ATRIP).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of ATR-interacting protein (ATRIP).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATR-interacting protein (ATRIP).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of ATR-interacting protein (ATRIP).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATR-interacting protein (ATRIP).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATR-interacting protein (ATRIP).	[15]

References

• [1] Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer.Urol Oncol. 2016 Mar;34(3):120.e9-16. doi: 10.1016/j.urolonc.2015.10.009. Epub 2015 Nov 14.
• [2] Human gastric adenocarcinoma cathepsin B: isolation and sequencing of full-length cDNAs and polymorphisms of the gene.Gene. 1994 Feb 25;139(2):163-9. doi: 10.1016/0378-1119(94)90750-1.
• [3] Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet. 2007 Apr;80(4):811-5. doi: 10.1086/513443. Epub 2007 Feb 19.
• [4] Inflammatory myopathy in a patient with Aicardi-Goutires syndrome.Eur J Med Genet. 2017 Mar;60(3):154-158. doi: 10.1016/j.ejmg.2016.12.004. Epub 2017 Jan 9.
• [5] Colonic Lysine Homocysteinylation Induced by High-Fat Diet Suppresses DNA Damage Repair.Cell Rep. 2018 Oct 9;25(2):398-412.e6. doi: 10.1016/j.celrep.2018.09.022.
• [6] The interaction between ATRIP and MCM complex is essential for ATRIP chromatin loading and its phosphorylation in mantle cell lymphoma cells.Pharmazie. 2017 Nov 1;72(11):670-673. doi: 10.1691/ph.2017.7676.
• [7] Phosphorylation of ATR-interacting protein on Ser239 mediates an interaction with breast-ovarian cancer susceptibility 1 and checkpoint function.Cancer Res. 2007 Jul 1;67(13):6100-5. doi: 10.1158/0008-5472.CAN-07-0369.
• [8] Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome. PLoS Genet. 2012;8(11):e1002945. doi: 10.1371/journal.pgen.1002945. Epub 2012 Nov 8.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.