Details of Drug Off-Target (DOT)

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

• DOT Name: UV excision repair protein RAD23 homolog A (RAD23A)
• Synonyms: HR23A; hHR23A
• Gene Name: RAD23A
• Related Disease:
  Advanced cancer
  Fragile X-associated tremor/ataxia syndrome
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Late-onset Parkinson disease
  Lung cancer
  Lung carcinoma
  Xeroderma pigmentosum
• UniProt ID: RD23A_HUMAN
• PDB ID: 1DV0; 1F4I; 1IFY; 1OQY; 1P98; 1P9D; 1QZE; 1TP4; 2WYQ; 5XBO; 6W2G; 6W2H; 6W2I; 6XQI; 6XQJ; 7TGP
• Pfam ID: PF00627 ; PF00240 ; PF09280
• Sequence:
  MAVTITLKTLQQQTFKIRMEPDETVKVLKEKIEAEKGRDAFPVAGQKLIYAGKILSDDVP
  IRDYRIDEKNFVVVMVTKTKAGQGTSAPPEASPTAAPESSTSFPPAPTSGMSHPPPAARE
  DKSPSEESAPTTSPESVSGSVPSSGSSGREEDAASTLVTGSEYETMLTEIMSMGYERERV
  VAALRASYNNPHRAVEYLLTGIPGSPEPEHGSVQESQVSEQPATEAAGENPLEFLRDQPQ
  FQNMRQVIQQNPALLPALLQQLGQENPQLLQQISRHQEQFIQMLNEPPGELADISDVEGE
  VGAIGEEAPQMNYIQVTPQEKEAIERLKALGFPESLVIQAYFACEKNENLAANFLLSQNF
  DDE
• Function: Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Binds to 'Lys-48'-linked polyubiquitin chains in a length-dependent manner and with a lower affinity to 'Lys-63'-linked polyubiquitin chains. Proposed to be capable to bind simultaneously to the 26S proteasome and to polyubiquitinated substrates and to deliver ubiquitinated proteins to the proteasome.; Involved in nucleotide excision repair and is thought to be functional equivalent for RAD23B in global genome nucleotide excision repair (GG-NER) by association with XPC. In vitro, the XPC:RAD23A dimer has NER activity. Can stabilize XPC.; (Microbial infection) Involved in Vpr-dependent replication of HIV-1 in non-proliferating cells and primary macrophages. Required for the association of HIV-1 Vpr with the host proteasome.
• KEGG Pathway:
  Nucleotide excision repair (hsa03420)
  Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  Josephin domain DUBs (R-HSA-5689877)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Fragile X-associated tremor/ataxia syndrome	DISKB25R	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[3]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[3]
Late-onset Parkinson disease	DIS9IOUI	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Xeroderma pigmentosum	DISQ9H19	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[11]
Marinol	DM70IK5	Approved	Marinol decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[17]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[23]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[17]
Indirubin-3'-monoxime	DMLRQH0	Investigative	Indirubin-3'-monoxime decreases the expression of UV excision repair protein RAD23 homolog A (RAD23A).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of UV excision repair protein RAD23 homolog A (RAD23A).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of UV excision repair protein RAD23 homolog A (RAD23A).	[24]

References

• [1] HR23A-knockdown lung cancer cells exhibit epithelial-to-mesenchymal transition and gain stemness properties through increased Twist1 stability.Biochim Biophys Acta Mol Cell Res. 2019 Dec;1866(12):118537. doi: 10.1016/j.bbamcr.2019.118537. Epub 2019 Sep 2.
• [2] The DNA repair-ubiquitin-associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair.Neurobiol Dis. 2006 Sep;23(3):708-16. doi: 10.1016/j.nbd.2006.06.005. Epub 2006 Jul 24.
• [3] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [4] C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins.Nat Neurosci. 2016 May;19(5):668-677. doi: 10.1038/nn.4272. Epub 2016 Mar 21.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in A549 adenocarcinoma cells. Toxicol Lett. 2011 Sep 10;205(3):341-50. doi: 10.1016/j.toxlet.2011.06.028. Epub 2011 Jul 2.
• [8] 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.
• [9] Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China. Toxicol Sci. 2001 Jan;59(1):185-92.
• [10] 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.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Gene expression changes in human small airway epithelial cells exposed to Delta9-tetrahydrocannabinol. Toxicol Lett. 2005 Aug 14;158(2):95-107.
• [13] 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.
• [14] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [15] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] Examining the genomic influence of skin antioxidants in vitro. Mediators Inflamm. 2010;2010.
• [18] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [19] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [20] 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.
• [21] Bisphenol-A impairs cellular function and alters DNA methylation of stress pathway genes in first trimester trophoblast cells. Reprod Toxicol. 2018 Dec;82:72-79.
• [22] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] 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.
• [25] The effects of indirubin-3'-monoxime, a novel AHR ligand, on stress and toxicity-related gene/protein expression in human U937 cells undergoing differentiation and activation. J Immunotoxicol. 2006 Jan 1;3(1):1-10.