Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT62LXE4)

DOT Name	Microprocessor complex subunit DGCR8 (DGCR8)
Synonyms	DiGeorge syndrome critical region 8
Gene Name	DGCR8
Related Disease	Congenital anomaly of kidney and urinary tract ( ) Acute coronary syndrome ( ) Advanced cancer ( ) Bone disease ( ) Breast carcinoma ( ) Childhood kidney Wilms tumor ( ) Congenital heart disease ( ) Dilated cardiomyopathy 1A ( ) Epithelial ovarian cancer ( ) Fragile X-associated tremor/ataxia syndrome ( ) Inflammatory breast cancer ( ) Invasive breast carcinoma ( ) Malignant neoplasm ( ) Mental disorder ( ) Multinodular goiter ( ) Multiple sclerosis ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Pneumonitis ( ) Precancerous condition ( ) Prostate cancer ( ) Prostate carcinoma ( ) Prostate neoplasm ( ) Psoriasis ( ) Psychotic disorder ( ) Relapsing-remitting multiple sclerosis ( ) Schizophrenia ( ) Schwannomatosis ( ) Shprintzen-Goldberg syndrome ( ) Skin cancer ( ) Tarsal-carpal coalition syndrome ( ) Tetralogy of fallot ( ) Transitional cell carcinoma ( ) Wilms tumor ( ) Bladder cancer ( ) Breast cancer ( ) DiGeorge syndrome ( ) Osteoarthritis ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Velocardiofacial syndrome ( ) Human papillomavirus infection ( ) Young-onset Parkinson disease ( )
UniProt ID	DGCR8_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1X47; 2YT4; 3LE4; 5B16; 6LXD; 6LXE; 6V5B; 6V5C; 7CNC
Pfam ID	PF00035
Sequence	METDESPSPLPCGPAGEAVMESRARPFQALPREQSPPPPLQTSSGAEVMDVGSGGDGQSE LPAEDPFNFYGASLLSKGSFSKGRLLIDPNCSGHSPRTARHAPAVRKFSPDLKLLKDVKI SVSFTESCRSKDRKVLYTGAERDVRAECGLLLSPVSGDVHACPFGGSVGDGVGIGGESAD KKDEENELDQEKRVEYAVLDELEDFTDNLELDEEGAGGFTAKAIVQRDRVDEEALNFPYE DDFDNDVDALLEEGLCAPKKRRTEEKYGGDSDHPSDGETSVQPMMTKIKTVLKSRGRPPT EPLPDGWIMTFHNSGVPVYLHRESRVVTWSRPYFLGTGSIRKHDPPLSSIPCLHYKKMKD NEEREQSSDLTPSGDVSPVKPLSRSAELEFPLDEPDSMGADPGPPDEKDPLGAEAAPGAL GQVKAKVEVCKDESVDLEEFRSYLEKRFDFEQVTVKKFRTWAERRQFNREMKRKQAESER PILPANQKLITLSVQDAPTKKEFVINPNGKSEVCILHEYMQRVLKVRPVYNFFECENPSE PFGASVTIDGVTYGSGTASSKKLAKNKAARATLEILIPDFVKQTSEEKPKDSEELEYFNH ISIEDSRVYELTSKAGLLSPYQILHECLKRNHGMGDTSIKFEVVPGKNQKSEYVMACGKH TVRGWCKNKRVGKQLASQKILQLLHPHVKNWGSLLRMYGRESSKMVKQETSDKSVIELQQ YAKKNKPNLHILSKLQEEMKRLAEEREETRKKPKMSIVASAQPGGEPLCTVDV
Function	Component of the microprocessor complex that acts as a RNA- and heme-binding protein that is involved in the initial step of microRNA (miRNA) biogenesis. Component of the microprocessor complex that is required to process primary miRNA transcripts (pri-miRNAs) to release precursor miRNA (pre-miRNA) in the nucleus. Within the microprocessor complex, DGCR8 function as a molecular anchor necessary for the recognition of pri-miRNA at dsRNA-ssRNA junction and directs DROSHA to cleave 11 bp away form the junction to release hairpin-shaped pre-miRNAs that are subsequently cut by the cytoplasmic DICER to generate mature miRNAs. The heme-bound DGCR8 dimer binds pri-miRNAs as a cooperative trimer (of dimers) and is active in triggering pri-miRNA cleavage, whereas the heme-free DGCR8 monomer binds pri-miRNAs as a dimer and is much less active. Both double-stranded and single-stranded regions of a pri-miRNA are required for its binding. Specifically recognizes and binds N6-methyladenosine (m6A)-containing pri-miRNAs, a modification required for pri-miRNAs processing. Involved in the silencing of embryonic stem cell self-renewal.
Tissue Specificity	Ubiquitously expressed.
Reactome Pathway	Transcriptional Regulation by MECP2 (R-HSA-8986944 ) MicroRNA (miRNA) biogenesis (R-HSA-203927 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Congenital anomaly of kidney and urinary tract	DIS84IVH	Definitive	Biomarker	[1]
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Bone disease	DISE1F82	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Biomarker	[6]
Congenital heart disease	DISQBA23	Strong	Altered Expression	[7]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Fragile X-associated tremor/ataxia syndrome	DISKB25R	Strong	Biomarker	[9]
Inflammatory breast cancer	DIS3QRWA	Strong	Altered Expression	[10]
Invasive breast carcinoma	DISANYTW	Strong	Altered Expression	[10]
Malignant neoplasm	DISS6SNG	Strong	Genetic Variation	[11]
Mental disorder	DIS3J5R8	Strong	Biomarker	[12]
Multinodular goiter	DISZQJH7	Strong	Genetic Variation	[11]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[13]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[8]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[8]
Pneumonitis	DIS88E0K	Strong	Genetic Variation	[14]
Precancerous condition	DISV06FL	Strong	Biomarker	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[17]
Psoriasis	DIS59VMN	Strong	Altered Expression	[18]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[19]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Altered Expression	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[19]
Schwannomatosis	DISDWAM1	Strong	Biomarker	[11]
Shprintzen-Goldberg syndrome	DISQH6P3	Strong	Genetic Variation	[20]
Skin cancer	DISTM18U	Strong	Biomarker	[15]
Tarsal-carpal coalition syndrome	DISY90L2	Strong	Biomarker	[21]
Tetralogy of fallot	DISMHFNW	Strong	Altered Expression	[7]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[21]
Wilms tumor	DISB6T16	Strong	Biomarker	[6]
Bladder cancer	DISUHNM0	moderate	Biomarker	[22]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[23]
DiGeorge syndrome	DIST1RKO	moderate	Genetic Variation	[20]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[24]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[22]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[22]
Velocardiofacial syndrome	DISOSBTY	moderate	Biomarker	[25]
Human papillomavirus infection	DISX61LX	Limited	Altered Expression	[26]
Young-onset Parkinson disease	DIS05LFS	Limited	Biomarker	[27]
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⏷ Show the Full List of 43 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Heme	DMGC287	Investigative	Microprocessor complex subunit DGCR8 (DGCR8) affects the binding of Heme.	[42]
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12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[28]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[30]
Selenium	DM25CGV	Approved	Selenium increases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[31]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[32]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[33]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[34]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[35]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[36]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[37]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[40]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Microprocessor complex subunit DGCR8 (DGCR8).	[41]
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⏷ Show the Full List of 12 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Microprocessor complex subunit DGCR8 (DGCR8).	[38]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Microprocessor complex subunit DGCR8 (DGCR8).	[39]
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References

1	Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract.Nephrol Dial Transplant. 2016 Aug;31(8):1280-3. doi: 10.1093/ndt/gfv447. Epub 2016 Jan 29.
2	Hyperglycemia Determines Increased Specific MicroRNAs Levels in Sera and HDL of Acute Coronary Syndrome Patients and Stimulates MicroRNAs Production in Human Macrophages.PLoS One. 2016 Aug 12;11(8):e0161201. doi: 10.1371/journal.pone.0161201. eCollection 2016.
3	Regulation of miRNA Biogenesis and Histone Modification by K63-Polyubiquitinated DDX17 Controls Cancer Stem-like Features.Cancer Res. 2019 May 15;79(10):2549-2563. doi: 10.1158/0008-5472.CAN-18-2376. Epub 2019 Mar 15.
4	Deficiency of DGCR8 increases bone formation through downregulation of miR-22 expression.Bone. 2017 Oct;103:287-294. doi: 10.1016/j.bone.2017.07.021. Epub 2017 Jul 21.
5	Upregulation of the double-stranded RNA binding protein DGCR8 in invasive ductal breast carcinoma.Gene. 2016 May 1;581(2):146-51. doi: 10.1016/j.gene.2016.01.033. Epub 2016 Jan 22.
6	Loss or oncogenic mutation of DROSHA impairs kidney development and function, but is not sufficient for Wilms tumor formation.Int J Cancer. 2019 Mar 15;144(6):1391-1400. doi: 10.1002/ijc.31952. Epub 2018 Dec 3.
7	DGCR8 expression is altered in children with congenital heart defects.Clin Chim Acta. 2019 Aug;495:25-28. doi: 10.1016/j.cca.2019.03.1619. Epub 2019 Mar 26.
8	Long noncoding RNA SNHG14 enhances migration and invasion of ovarian cancer by upregulating DGCR8.Eur Rev Med Pharmacol Sci. 2019 Dec;23(23):10226-10233. doi: 10.26355/eurrev_201912_19659.
9	Sequestration of DROSHA and DGCR8 by expanded CGG RNA repeats alters microRNA processing in fragile X-associated tremor/ataxia syndrome.Cell Rep. 2013 Mar 28;3(3):869-80. doi: 10.1016/j.celrep.2013.02.004. Epub 2013 Mar 7.
10	Complexity in regulation of microRNA machinery components in invasive breast carcinoma.Pathol Oncol Res. 2014 Jul;20(3):697-705. doi: 10.1007/s12253-014-9750-5. Epub 2014 Feb 27.
11	DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis.J Clin Invest. 2020 Mar 2;130(3):1479-1490. doi: 10.1172/JCI130206.
12	Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model.Nat Genet. 2008 Jun;40(6):751-60. doi: 10.1038/ng.138. Epub 2008 May 11.
13	Overexpression of microRNA biogenesis machinery: Drosha, DGCR8 and Dicer in multiple sclerosis patients.J Clin Neurosci. 2015 Jan;22(1):200-3. doi: 10.1016/j.jocn.2014.06.106. Epub 2014 Oct 30.
14	MiRNA-Related Genetic Variations Associated with Radiotherapy-Induced Toxicities in Patients with Locally Advanced Non-Small Cell Lung Cancer.PLoS One. 2016 Mar 18;11(3):e0150467. doi: 10.1371/journal.pone.0150467. eCollection 2016.
15	Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1, and TARBP2 in epithelial skin cancer.Mol Carcinog. 2012 Nov;51(11):916-22. doi: 10.1002/mc.20861. Epub 2011 Oct 24.
16	Long noncoding RNA TUG1 promotes progression via upregulating DGCR8 in prostate cancer.Eur Rev Med Pharmacol Sci. 2019 Mar;23(6):2391-2398. doi: 10.26355/eurrev_201903_17385.
17	DGCR8 is essential for tumor progression following PTEN loss in the prostate.EMBO Rep. 2015 Sep;16(9):1219-32. doi: 10.15252/embr.201439925. Epub 2015 Jul 23.
18	Overexpression of Drosha, DiGeorge syndrome critical region gene 8 (DGCR8), and Dicer mRNAs in the pathogenesis of psoriasis.J Cosmet Dermatol. 2017 Dec;16(4):e48-e53. doi: 10.1111/jocd.12336. Epub 2017 Mar 25.
19	Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models.Science. 2014 Jun 6;344(6188):1178-82. doi: 10.1126/science.1253895.
20	Deletion of DGCR8 in VSMCs of adult mice results in loss of vascular reactivity, reduced blood pressure and neointima formation.Sci Rep. 2018 Jan 23;8(1):1468. doi: 10.1038/s41598-018-19660-z.
21	Downregulation of Dicer, a component of the microRNA machinery, in bladder cancer.Mol Med Rep. 2012 Mar;5(3):695-9. doi: 10.3892/mmr.2011.711. Epub 2011 Dec 14.
22	METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner.Mol Cancer. 2019 Jun 22;18(1):110. doi: 10.1186/s12943-019-1036-9.
23	Evaluation of genetic variants in microRNA biosynthesis genes and risk of breast cancer in Chinese women.Int J Cancer. 2013 Nov;133(9):2216-24. doi: 10.1002/ijc.28237. Epub 2013 Jul 11.
24	Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis.Nat Commun. 2019 Jul 26;10(1):3329. doi: 10.1038/s41467-019-10831-8.
25	Molecular cloning and expression analysis of a novel gene DGCR8 located in the DiGeorge syndrome chromosomal region.Biochem Biophys Res Commun. 2003 Apr 25;304(1):184-90. doi: 10.1016/s0006-291x(03)00554-0.
26	HPV shapes tumor transcriptome by globally modifying the pool of RNA binding protein-binding motif.Aging (Albany NY). 2019 Apr 29;11(8):2430-2446. doi: 10.18632/aging.101927.
27	Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications.JAMA Neurol. 2013 Nov;70(11):1359-66. doi: 10.1001/jamaneurol.2013.3646.
28	Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
29	Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
30	Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
31	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
32	miR-148a/LDLR mediates hypercholesterolemia induced by prenatal dexamethasone exposure in male offspring rats. Toxicol Appl Pharmacol. 2020 May 15;395:114979. doi: 10.1016/j.taap.2020.114979. Epub 2020 Mar 29.
33	Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
34	Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
35	Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
36	Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
37	Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
38	Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
39	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.
40	Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
41	Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
42	DiGeorge critical region 8 (DGCR8) is a double-cysteine-ligated heme protein. J Biol Chem. 2011 May 13;286(19):16716-25. doi: 10.1074/jbc.M110.180844. Epub 2011 Mar 21.