Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ZDVOE)

• DOT Name: DDB1- and CUL4-associated factor 1 (DCAF1)
• Synonyms: HIV-1 Vpr-binding protein; VprBP; Serine/threonine-protein kinase VPRBP; EC 2.7.11.1; Vpr-interacting protein
• Gene Name: DCAF1
• Related Disease:
  Hepatocellular carcinoma
  Melanoma
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Colitis
  Colon cancer
  Colon carcinoma
  Diabetic neuropathy
  Estrogen-receptor positive breast cancer
  Gaucher disease
  Glioma
  Herpes simplex infection
  Non-small-cell lung cancer
  Osteosarcoma
  Pancreatic cancer
  Pancreatic tumour
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Small lymphocytic lymphoma
  Systemic lupus erythematosus
  Type-1/2 diabetes
  Ulcerative colitis
  Allergic rhinitis
  Gallbladder cancer
  Hypoglycemia
  Plasma cell myeloma
  Carcinoma of liver and intrahepatic biliary tract
  Clear cell renal carcinoma
  Congenital contractural arachnodactyly
  Hepatitis C virus infection
  Hyperglycemia
  Liver cancer
  Nasopharyngeal carcinoma
  Neoplasm
  Neuroendocrine neoplasm
  Neurofibromatosis type 2
  Renal cell carcinoma
  Schwannoma
• UniProt ID: DCAF1_HUMAN
• PDB ID: 3WA0; 4CC9; 4P7I; 4PXW; 4Z8L; 5AJA; 5JK7; 6N45; 6ZUE; 6ZX9; 7OKQ; 7SSE; 7UFV; 7V7B; 7V7C; 8F8E; 8OG5; 8OG6; 8OG7; 8OG8; 8OG9; 8OGA; 8OGB; 8OGC; 8OO5; 8OOD
• EC Number: 2.7.11.1
• Sequence:
  MTTVVVHVDSKAELTTLLEQWEKEHGSGQDMVPILTRMSQLIEKETEEYRKGDPDPFDDR
  HPGRADPECMLGHLLRILFKNDDFMNALVNAYVMTSREPPLNTAACRLLLDIMPGLETAV
  VFQEKEGIVENLFKWAREADQPLRTYSTGLLGGAMENQDIAANYRDENSQLVAIVLRRLR
  ELQLQEVALRQENKRPSPRKLSSEPLLPLDEEAVDMDYGDMAVDVVDGDQEEASGDMEIS
  FHLDSGHKTSSRVNSTTKPEDGGLKKNKSAKQGDRENFRKAKQKLGFSSSDPDRMFVELS
  NSSWSEMSPWVIGTNYTLYPMTPAIEQRLILQYLTPLGEYQELLPIFMQLGSRELMMFYI
  DLKQTNDVLLTFEALKHLASLLLHNKFATEFVAHGGVQKLLEIPRPSMAATGVSMCLYYL
  SYNQDAMERVCMHPHNVLSDVVNYTLWLMECSHASGCCHATMFFSICFSFRAVLELFDRY
  DGLRRLVNLISTLEILNLEDQGALLSDDEIFASRQTGKHTCMALRKYFEAHLAIKLEQVK
  QSLQRTEGGILVHPQPPYKACSYTHEQIVEMMEFLIEYGPAQLYWEPAEVFLKLSCVQLL
  LQLISIACNWKTYYARNDTVRFALDVLAILTVVPKIQLQLAESVDVLDEAGSTVSTVGIS
  IILGVAEGEFFIHDAEIQKSALQIIINCVCGPDNRISSIGKFISGTPRRKLPQNPKSSEH
  TLAKMWNVVQSNNGIKVLLSLLSIKMPITDADQIRALACKALVGLSRSSTVRQIISKLPL
  FSSCQIQQLMKEPVLQDKRSDHVKFCKYAAELIERVSGKPLLIGTDVSLARLQKADVVAQ
  SRISFPEKELLLLIRNHLISKGLGETATVLTKEADLPMTAASHSSAFTPVTAAASPVSLP
  RTPRIANGIATRLGSHAAVGASAPSAPTAHPQPRPPQGPLALPGPSYAGNSPLIGRISFI
  RERPSPCNGRKIRVLRQKSDHGAYSQSPAIKKQLDRHLPSPPTLDSIITEYLREQHARCK
  NPVATCPPFSLFTPHQCPEPKQRRQAPINFTSRLNRRASFPKYGGVDGGCFDRHLIFSRF
  RPISVFREANEDESGFTCCAFSARERFLMLGTCTGQLKLYNVFSGQEEASYNCHNSAITH
  LEPSRDGSLLLTSATWSQPLSALWGMKSVFDMKHSFTEDHYVEFSKHSQDRVIGTKGDIA
  HIYDIQTGNKLLTLFNPDLANNYKRNCATFNPTDDLVLNDGVLWDVRSAQAIHKFDKFNM
  NISGVFHPNGLEVIINTEIWDLRTFHLLHTVPALDQCRVVFNHTGTVMYGAMLQADDEDD
  LMEERMKSPFGSSFRTFNATDYKPIATIDVKRNIFDLCTDTKDCYLAVIENQGSMDALNM
  DTVCRLYEVGRQRLAEDEDEEEDQEEEEQEEEDDDEDDDDTDDLDELDTDQLLEAELEED
  DNNENAGEDGDNDFSPSDEELANLLEEGEDGEDEDSDADEEVELILGDTDSSDNSDLEDD
  IILSLNE
• Function: Acts both as a substrate recognition component of E3 ubiquitin-protein ligase complexes and as an atypical serine/threonine-protein kinase, playing key roles in various processes such as cell cycle, telomerase regulation and histone modification. Probable substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, named CUL4A-RBX1-DDB1-DCAF1/VPRBP complex, which mediates ubiquitination and proteasome-dependent degradation of proteins such as NF2. Involved in the turnover of methylated proteins: recognizes and binds methylated proteins via its chromo domain, leading to ubiquitination of target proteins by the RBX1-DDB1-DCAF1/VPRBP complex. The CUL4A-RBX1-DDB1-DCAF1/VPRBP complex is also involved in B-cell development: DCAF1 is recruited by RAG1 to ubiquitinate proteins, leading to limit error-prone repair during V(D)J recombination. Also part of the EDVP complex, an E3 ligase complex that mediates ubiquitination of proteins such as TERT, leading to TERT degradation and telomerase inhibition. Also acts as an atypical serine/threonine-protein kinase that specifically mediates phosphorylation of 'Thr-120' of histone H2A (H2AT120ph) in a nucleosomal context, thereby repressing transcription. H2AT120ph is present in the regulatory region of many tumor suppresor genes, down-regulates their transcription and is present at high level in a number of tumors. Involved in JNK-mediated apoptosis during cell competition process via its interaction with LLGL1 and LLGL2. By acting on TET dioxygenses, essential for oocyte maintenance at the primordial follicle stage, hence essential for female fertility; (Microbial infection) In case of infection by HIV-1 virus, it is recruited by HIV-1 Vpr in order to hijack the CUL4A-RBX1-DDB1-DCAF1/VPRBP function leading to arrest the cell cycle in G2 phase, and also to protect the viral protein from proteasomal degradation by another E3 ubiquitin ligase. The HIV-1 Vpr protein hijacks the CUL4A-RBX1-DDB1-DCAF1/VPRBP complex to promote ubiquitination and degradation of proteins such as TERT and ZIP/ZGPAT; (Microbial infection) In case of infection by HIV-2 virus, it is recruited by HIV-2 Vpx in order to hijack the CUL4A-RBX1-DDB1-DCAF1/VPRBP function leading to enhanced efficiency of macrophage infection and promotion of the replication of cognate primate lentiviruses in cells of monocyte/macrophage lineage.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Melanoma	DIS1RRCY	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Colitis	DISAF7DD	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Genetic Variation	[9]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[9]
Diabetic neuropathy	DISX6VF8	Strong	Biomarker	[10]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[5]
Gaucher disease	DISTW5JG	Strong	Biomarker	[11]
Glioma	DIS5RPEH	Strong	Altered Expression	[12]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[14]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Pancreatic cancer	DISJC981	Strong	Biomarker	[15]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[17]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[17]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[18]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[19]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[20]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[21]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[22]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[23]
Gallbladder cancer	DISXJUAF	moderate	Biomarker	[24]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[25]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[26]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[27]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[28]
Congenital contractural arachnodactyly	DISOM1K7	Limited	Biomarker	[29]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[30]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[31]
Liver cancer	DISDE4BI	Limited	Biomarker	[27]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[32]
Neoplasm	DISZKGEW	Limited	Biomarker	[33]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[34]
Neurofibromatosis type 2	DISI8ECS	Limited	Genetic Variation	[35]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[28]
Schwannoma	DISTTVLA	Limited	Biomarker	[36]

5 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 DDB1- and CUL4-associated factor 1 (DCAF1).	[37]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DDB1- and CUL4-associated factor 1 (DCAF1).	[38]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DDB1- and CUL4-associated factor 1 (DCAF1).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DDB1- and CUL4-associated factor 1 (DCAF1).	[40]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of DDB1- and CUL4-associated factor 1 (DCAF1).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DDB1- and CUL4-associated factor 1 (DCAF1).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DDB1- and CUL4-associated factor 1 (DCAF1).	[42]

References

• [1] Long non-coding RNA SNHG1 functions as a competitive endogenous RNA to regulate PDCD4 expression by sponging miR-195-5p in hepatocellular carcinoma.Gene. 2019 Sep 25;714:143994. doi: 10.1016/j.gene.2019.143994. Epub 2019 Jul 19.
• [2] Long non-coding RNA H19 promotes glucose metabolism and cell growth in malignant melanoma via miR-106a-5p/E2F3 axis.J Cancer Res Clin Oncol. 2018 Mar;144(3):531-542. doi: 10.1007/s00432-018-2582-z. Epub 2018 Jan 19.
• [3] RIP Kinases in Liver Cell Death, Inflammation and Cancer.Trends Mol Med. 2019 Jan;25(1):47-63. doi: 10.1016/j.molmed.2018.10.007. Epub 2018 Nov 16.
• [4] Long noncoding RNA NEAT1 regulates the development of osteosarcoma through sponging miR-34a-5p to mediate HOXA13 expression as a competitive endogenous RNA.Mol Genet Genomic Med. 2019 Jun;7(6):e673. doi: 10.1002/mgg3.673. Epub 2019 May 1.
• [5] The RNA binding protein HuR differentially regulates unique subsets of mRNAs in estrogen receptor negative and estrogen receptor positive breast cancer.BMC Cancer. 2010 Apr 6;10:126. doi: 10.1186/1471-2407-10-126.
• [6] Down-regulation of RIP expression by 17-dimethylaminoethylamino-17-demethoxygeldanamycin promotes TRAIL-induced apoptosis in breast tumor cells.Cancer Lett. 2010 Jan 28;287(2):207-15. doi: 10.1016/j.canlet.2009.06.012. Epub 2009 Jul 25.
• [7] LncRNA STXBP5-AS1 suppressed cervical cancer progression via targeting miR-96-5p/PTEN axis.Biomed Pharmacother. 2019 Sep;117:109082. doi: 10.1016/j.biopha.2019.109082. Epub 2019 Jun 15.
• [8] Ameliorating effect of TI-1-162, a hydroxyindenone derivative, against TNBS-induced rat colitis is mediated through suppression of RIP/ASK-1/MAPK signaling.Eur J Pharmacol. 2018 May 15;827:94-102. doi: 10.1016/j.ejphar.2018.03.027. Epub 2018 Mar 16.
• [9] Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) to promote colon cancer development.Cancer Lett. 2016 Jun 1;375(2):209-220. doi: 10.1016/j.canlet.2016.02.055. Epub 2016 Mar 7.
• [10] Diabetic neuropathy: electrophysiological and morphological study of peripheral nerve degeneration and regeneration in transgenic mice that express IFNbeta in beta cells.Muscle Nerve. 2010 May;41(5):630-41. doi: 10.1002/mus.21564.
• [11] Emerging therapeutic targets for Gaucher disease.Expert Opin Ther Targets. 2015 Mar;19(3):321-34. doi: 10.1517/14728222.2014.981530. Epub 2014 Nov 21.
• [12] Long Non-Coding RNA HOXA-AS2 Enhances The Malignant Biological Behaviors In Glioma By Epigenetically Regulating RND3 Expression.Onco Targets Ther. 2019 Nov 7;12:9407-9419. doi: 10.2147/OTT.S225678. eCollection 2019.
• [13] Suppression of RIP3-dependent necroptosis by human cytomegalovirus.J Biol Chem. 2015 May 1;290(18):11635-48. doi: 10.1074/jbc.M115.646042. Epub 2015 Mar 16.
• [14] Long noncoding RNA PCAT6 functions as an oncogene by binding to EZH2 and suppressing LATS2 in non-small-cell lung cancer.EBioMedicine. 2018 Nov;37:177-187. doi: 10.1016/j.ebiom.2018.10.004. Epub 2018 Oct 9.
• [15] Effective ablation of pancreatic cancer cells in SCID mice using systemic adenoviral RIP-TK/GCV gene therapy.J Surg Res. 2007 Jul;141(1):45-52. doi: 10.1016/j.jss.2007.02.041. Epub 2007 May 18.
• [16] Non-invasive MRI tumor imaging and synergistic anticancer effect of HSP90 inhibitor and glycolysis inhibitor in RIP1-Tag2 transgenic pancreatic tumor model.Cancer Chemother Pharmacol. 2008 Nov;62(6):985-94. doi: 10.1007/s00280-008-0688-8. Epub 2008 Feb 6.
• [17] Stroma-induced Jagged1 expression drives PC3 prostate cancer cell migration; disparate effects of RIP-generated proteolytic fragments on cell behaviour and Notch signaling.Biochem Biophys Res Commun. 2016 Mar 25;472(1):255-61. doi: 10.1016/j.bbrc.2016.02.101. Epub 2016 Feb 26.
• [18] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [19] Mutation analysis of the FAS and TNFR apoptotic cascade genes in hematological malignancies.Exp Hematol. 2001 Feb;29(2):228-33. doi: 10.1016/s0301-472x(00)00623-8.
• [20] Altered expression of TNF-alpha signaling pathway proteins in systemic lupus erythematosus.J Rheumatol. 2010 Aug 1;37(8):1658-66. doi: 10.3899/jrheum.091123. Epub 2010 Jun 1.
• [21] Targeting Innate Immunity for Type 1 Diabetes Prevention.Curr Diab Rep. 2017 Sep 27;17(11):113. doi: 10.1007/s11892-017-0930-z.
• [22] Dihydrotanshinone I, a natural product, ameliorates DSS-induced experimental ulcerative colitis in mice.Toxicol Appl Pharmacol. 2018 Apr 1;344:35-45. doi: 10.1016/j.taap.2018.02.018. Epub 2018 Feb 27.
• [23] Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.Nat Genet. 2018 Aug;50(8):1072-1080. doi: 10.1038/s41588-018-0157-1. Epub 2018 Jul 16.
• [24] Expression of the RIP-1 gene and its role in growth and invasion of human gallbladder carcinoma.Cell Physiol Biochem. 2014;34(4):1152-65. doi: 10.1159/000366328. Epub 2014 Sep 22.
• [25] Extended life span is associated with insulin resistance in a transgenic mouse model of insulinoma secreting human islet amyloid polypeptide.Am J Physiol Endocrinol Metab. 2004 Mar;286(3):E418-24. doi: 10.1152/ajpendo.00137.2003. Epub 2003 Nov 12.
• [26] LncRNA MALAT-1 Elevates HMGB1 to Promote Autophagy Resulting in Inhibition of Tumor Cell Apoptosis in Multiple Myeloma.J Cell Biochem. 2017 Oct;118(10):3341-3348. doi: 10.1002/jcb.25987. Epub 2017 May 3.
• [27] Protective effect of RIP and c-FLIP in preventing liver cancer cell apoptosis induced by TRAIL.Int J Clin Exp Pathol. 2015 Jun 1;8(6):6519-25. eCollection 2015.
• [28] Androgen receptor regulates ASS1P3/miR-34a-5p/ASS1 signaling to promote renal cell carcinoma cell growth.Cell Death Dis. 2019 Apr 18;10(5):339. doi: 10.1038/s41419-019-1330-x.
• [29] LncRNA FENDRR represses proliferation, migration and invasion through suppression of survivin in cholangiocarcinoma cells.Cell Cycle. 2019 Apr;18(8):889-897. doi: 10.1080/15384101.2019.1598726. Epub 2019 Apr 14.
• [30] DCAF1 is involved in HCV replication through regulation of miR-122.Arch Virol. 2018 Apr;163(4):977-985. doi: 10.1007/s00705-017-3691-8. Epub 2018 Jan 11.
• [31] The diabetogenic, insulin-specific CD8 T cell response primed in the experimental autoimmune diabetes model in RIP-B7.1 mice.Eur J Immunol. 2007 Aug;37(8):2097-103. doi: 10.1002/eji.200737222.
• [32] Long non-coding RNA LINC01133 mediates nasopharyngeal carcinoma tumorigenesis by binding to YBX1.Am J Cancer Res. 2019 Apr 1;9(4):779-790. eCollection 2019.
• [33] Parallel Signaling through IRE1 and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival.Cancer Res. 2019 Dec 15;79(24):6190-6203. doi: 10.1158/0008-5472.CAN-19-1116. Epub 2019 Oct 31.
• [34] Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms.Cancer Res. 2018 Feb 15;78(4):922-937. doi: 10.1158/0008-5472.CAN-15-3308. Epub 2017 Dec 19.
• [35] Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis.Mol Cancer Ther. 2017 Aug;16(8):1693-1704. doi: 10.1158/1535-7163.MCT-16-0821. Epub 2017 May 3.
• [36] The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors.Oncogene. 2016 Jun 30;35(26):3443-53. doi: 10.1038/onc.2015.404. Epub 2015 Nov 9.
• [37] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [38] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [39] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [40] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [41] 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.
• [42] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [43] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.