Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTC0Z9Y)

• DOT Name: BRCA1-associated RING domain protein 1 (BARD1)
• Synonyms: BARD-1; EC 2.3.2.27; RING-type E3 ubiquitin transferase BARD1
• Gene Name: BARD1
• Related Disease:
  Acute myelogenous leukaemia
  HER2/NEU overexpressing breast cancer
  Hereditary breast carcinoma
  Neuroblastoma
  Bone osteosarcoma
  Colon cancer
  Colon carcinoma
  Endometrial carcinoma
  Estrogen-receptor positive breast cancer
  Hepatocellular carcinoma
  Hereditary breast ovarian cancer syndrome
  Malignant uterine tumour
  Nasopharyngeal carcinoma
  Non-small-cell lung cancer
  Osteosarcoma
  Precancerous condition
  Pulmonary fibrosis
  Wilms tumor
  Fallopian tube cancer
  Fallopian tube carcinoma
  Hereditary neoplastic syndrome
  Aplasia cutis congenita
  Breast neoplasm
  Clear cell adenocarcinoma
  Corpus callosum, agenesis of
  Familial ovarian cancer
  Hereditary nonpolyposis colon cancer
  Lynch syndrome 1
  Lynch syndrome 2
  Triple negative breast cancer
• UniProt ID: BARD1_HUMAN
• PDB ID: 1JM7; 2NTE; 2R1Z; 3C5R; 3FA2; 6M14; 7E8I; 7JZV; 7LYB; 7LYC; 8GRQ
• EC Number: 2.3.2.27
• Pfam ID: PF12796 ; PF00533 ; PF14835
• Sequence:
  MPDNRQPRNRQPRIRSGNEPRSAPAMEPDGRGAWAHSRAALDRLEKLLRCSRCTNILREP
  VCLGGCEHIFCSNCVSDCIGTGCPVCYTPAWIQDLKINRQLDSMIQLCSKLRNLLHDNEL
  SDLKEDKPRKSLFNDAGNKKNSIKMWFSPRSKKVRYVVSKASVQTQPAIKKDASAQQDSY
  EFVSPSPPADVSERAKKASARSGKKQKKKTLAEINQKWNLEAEKEDGEFDSKEESKQKLV
  SFCSQPSVISSPQINGEIDLLASGSLTESECFGSLTEVSLPLAEQIESPDTKSRNEVVTP
  EKVCKNYLTSKKSLPLENNGKRGHHNRLSSPISKRCRTSILSTSGDFVKQTVPSENIPLP
  ECSSPPSCKRKVGGTSGRKNSNMSDEFISLSPGTPPSTLSSSSYRRVMSSPSAMKLLPNM
  AVKRNHRGETLLHIASIKGDIPSVEYLLQNGSDPNVKDHAGWTPLHEACNHGHLKVVELL
  LQHKALVNTTGYQNDSPLHDAAKNGHVDIVKLLLSYGASRNAVNIFGLRPVDYTDDESMK
  SLLLLPEKNESSSASHCSVMNTGQRRDGPLVLIGSGLSSEQQKMLSELAVILKAKKYTEF
  DSTVTHVVVPGDAVQSTLKCMLGILNGCWILKFEWVKACLRRKVCEQEEKYEIPEGPRRS
  RLNREQLLPKLFDGCYFYLWGTFKHHPKDNLIKLVTAGGGQILSRKPKPDSDVTQTINTV
  AYHARPDSDQRFCTQYIIYEDLCNYHPERVRQGKVWKAPSSWFIDCVMSFELLPLDS
• Function: E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.
• KEGG Pathway: Homologous recombi.tion (hsa03440)
• Reactome Pathway:
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  UCH proteinases (R-HSA-5689603)
  Metalloprotease DUBs (R-HSA-5689901)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Defective DNA double strand break response due to BRCA1 loss of function (R-HSA-9663199)
  Defective DNA double strand break response due to BARD1 loss of function (R-HSA-9699150)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
HER2/NEU overexpressing breast cancer	DISYKID5	Definitive	Genetic Variation	[2]
Hereditary breast carcinoma	DISAEZT5	Definitive	Autosomal dominant	[3]
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[7]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Hereditary breast ovarian cancer syndrome	DISWDUGU	Strong	CausalMutation	[10]
Malignant uterine tumour	DIS3QDT8	Strong	Genetic Variation	[11]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Precancerous condition	DISV06FL	Strong	Biomarker	[14]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[15]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[16]
Fallopian tube cancer	DISXHWCS	moderate	Genetic Variation	[17]
Fallopian tube carcinoma	DIST7A80	moderate	Genetic Variation	[17]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	CausalMutation	[18]
Aplasia cutis congenita	DISMDAYM	Limited	Altered Expression	[19]
Breast neoplasm	DISNGJLM	Limited	Genetic Variation	[20]
Clear cell adenocarcinoma	DISYUGHZ	Limited	Altered Expression	[21]
Corpus callosum, agenesis of	DISO9P40	Limited	Altered Expression	[19]
Familial ovarian cancer	DISGLR2C	Limited	Autosomal dominant	[3]
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Autosomal dominant	[3]
Lynch syndrome 1	DISSABLZ	Limited	Biomarker	[6]
Lynch syndrome 2	DISRLYU1	Limited	Biomarker	[6]
Triple negative breast cancer	DISAMG6N	Limited	Genetic Variation	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	BRCA1-associated RING domain protein 1 (BARD1) increases the response to substance of Bortezomib.	[48]

27 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 BRCA1-associated RING domain protein 1 (BARD1).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[28]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[29]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[29]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of BRCA1-associated RING domain protein 1 (BARD1).	[30]
Selenium	DM25CGV	Approved	Selenium decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[31]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[32]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[33]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of BRCA1-associated RING domain protein 1 (BARD1).	[30]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[34]
Daunorubicin	DMQUSBT	Approved	Daunorubicin affects the expression of BRCA1-associated RING domain protein 1 (BARD1).	[35]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[36]
Bicalutamide	DMZMSPF	Approved	Bicalutamide decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[37]
LY2835219	DM93VBZ	Approved	LY2835219 decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[38]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[39]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[31]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[44]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[45]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[46]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of BRCA1-associated RING domain protein 1 (BARD1).	[47]

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 BRCA1-associated RING domain protein 1 (BARD1).	[42]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of BRCA1-associated RING domain protein 1 (BARD1).	[43]

References

• [1] HDAC inhibitors repress BARD1 isoform expression in acute myeloid leukemia cells via activation of miR-19a and/or b.PLoS One. 2013 Dec 11;8(12):e83018. doi: 10.1371/journal.pone.0083018. eCollection 2013.
• [2] Germline single nucleotide polymorphisms in ERBB3 and BARD1 genes result in a worse relapse free survival response for HER2-positive breast cancer patients treated with adjuvant based docetaxel, carboplatin and trastuzumab (TCH).PLoS One. 2018 Aug 2;13(8):e0200996. doi: 10.1371/journal.pone.0200996. eCollection 2018.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Exploring Shared Susceptibility between Two Neural Crest Cells Originating Conditions: Neuroblastoma and Congenital Heart Disease.Genes (Basel). 2019 Aug 30;10(9):663. doi: 10.3390/genes10090663.
• [5] Long-term Outcome After Doxorubicin and Ifosfamide Overdose in a Patient With Osteosarcoma and BARD1 Mutation.J Pediatr Hematol Oncol. 2019 Mar;41(2):e94-e96. doi: 10.1097/MPH.0000000000001264.
• [6] Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer.Sci Rep. 2016 May 20;6:26273. doi: 10.1038/srep26273.
• [7] BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition.Eur J Hum Genet. 2006 Feb;14(2):167-72. doi: 10.1038/sj.ejhg.5201542.
• [8] Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1.Nat Commun. 2018 Apr 23;9(1):1595. doi: 10.1038/s41467-018-03951-0.
• [9] Up-regulation of BRCA1-associated RING Domain 1 Promotes Hepatocellular Carcinoma Progression by Targeting Akt Signaling.Sci Rep. 2017 Aug 9;7(1):7649. doi: 10.1038/s41598-017-07962-7.
• [10] BARD1 nonsense variant c.1921C>T in a patient with recurrent breast cancer.Clin Case Rep. 2017 Jan 4;5(2):104-107. doi: 10.1002/ccr3.793. eCollection 2017 Feb.
• [11] Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis.Int J Cancer. 2006 Mar 1;118(5):1215-26. doi: 10.1002/ijc.21428.
• [12] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [13] BARD1: an independent predictor of survival in non-small cell lung cancer.Int J Cancer. 2012 Jul 1;131(1):83-94. doi: 10.1002/ijc.26346. Epub 2011 Dec 21.
• [14] In vitro repression of Brca1-associated RING domain gene, Bard1, induces phenotypic changes in mammary epithelial cells.J Cell Biol. 1998 Nov 30;143(5):1329-39. doi: 10.1083/jcb.143.5.1329.
• [15] BARD1 mediates TGF- signaling in pulmonary fibrosis.Respir Res. 2015 Sep 29;16:118. doi: 10.1186/s12931-015-0278-3.
• [16] BARD1 Gene Polymorphisms Confer Nephroblastoma Susceptibility.EBioMedicine. 2017 Feb;16:101-105. doi: 10.1016/j.ebiom.2017.01.038. Epub 2017 Jan 31.
• [17] Challenges in Interpreting Germline Mutations in BARD1 and ATM in Breast and Ovarian Cancer Patients.Breast J. 2017 Jul;23(4):461-464. doi: 10.1111/tbj.12764. Epub 2017 Jan 31.
• [18] Multi-gene panel testing for hereditary cancer predisposition in unsolved high-risk breast and ovarian cancer patients.Breast Cancer Res Treat. 2017 Jun;163(2):383-390. doi: 10.1007/s10549-017-4181-0. Epub 2017 Mar 9.
• [19] Immunohistochemical validation of overexpressed genes identified by global expression microarrays in adrenocortical carcinoma reveals potential predictive and prognostic biomarkers.Oncologist. 2015 Mar;20(3):247-56. doi: 10.1634/theoncologist.2014-0392. Epub 2015 Feb 5.
• [20] BARD1 and breast cancer in Poland.Breast Cancer Res Treat. 2008 Jan;107(1):119-22. doi: 10.1007/s10549-007-9537-4. Epub 2007 Feb 27.
• [21] Oncogenic BARD1 isoforms expressed in gynecological cancers.Cancer Res. 2007 Dec 15;67(24):11876-85. doi: 10.1158/0008-5472.CAN-07-2370.
• [22] Landscape of pathogenic variations ina panel of 34 genes and cancer risk estimation from 5131 HBOC families.Genet Med. 2018 Dec;20(12):1677-1686. doi: 10.1038/s41436-018-0005-9. Epub 2018 Jul 10.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [25] Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways. Chem Biol Interact. 2023 Feb 1;371:110342. doi: 10.1016/j.cbi.2023.110342. Epub 2023 Jan 10.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [28] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [29] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [30] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [33] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [34] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [35] Daunorubicin-induced variations in gene transcription: commitment to proliferation arrest, senescence and apoptosis. Biochem J. 2003 Jun 15;372(Pt 3):703-11. doi: 10.1042/BJ20021950.
• [36] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [37] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [38] Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget. 2017 Jul 4;8(27):43678-43691. doi: 10.18632/oncotarget.18435.
• [39] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [40] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [41] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [42] 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.
• [43] 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.
• [44] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [45] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [46] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [47] 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.
• [48] Suppression of BRCA1 sensitizes cells to proteasome inhibitors. Cell Death Dis. 2014 Dec 18;5(12):e1580. doi: 10.1038/cddis.2014.537.