Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ERFFQ)

• DOT Name: E3 ubiquitin-protein ligase Topors (TOPORS)
• Synonyms: EC 2.3.2.27; RING-type E3 ubiquitin transferase Topors; SUMO1-protein E3 ligase Topors; Topoisomerase I-binding RING finger protein; Topoisomerase I-binding arginine/serine-rich protein; Tumor suppressor p53-binding protein 3; p53-binding protein 3; p53BP3
• Gene Name: TOPORS
• Related Disease:
  Inherited retinal dystrophy
  Retinitis pigmentosa 31
  Alzheimer disease
  Childhood acute lymphoblastic leukemia
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Osteosarcoma
  Retinitis pigmentosa
  Acute myelogenous leukaemia
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
• UniProt ID: TOPRS_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00097
• Sequence:
  MGSQPPLGSPLSREEGEAPPPAPASEGRRRSRRVRLRGSCRHRPSFLGCRELAASAPARP
  APASSEIMASAAKEFKMDNFSPKAGTSKLQQTVPADASPDSKCPICLDRFDNVSYLDRCL
  HKFCFRCVQEWSKNKAECPLCKQPFDSIFHSVRAEDDFKEYVLRPSYNGSFVTPDRRFRY
  RTTLTRERNASVYSPSGPVNRRTTTPPDSGVLFEGLGISTRPRDVEIPQFMRQIAVRRPT
  TADERSLRKIQEQDIINFRRTLYRAGARVRNIEDGGRYRDISAEFFRRNPACLHRLVPWL
  KRELTVLFGAHGSLVNIVQHIIMSNVTRYDLESQAFVSDLRPFLLNRTEHFIHEFISFAR
  SPFNMAAFDQHANYDCPAPSYEEGSHSDSSVITISPDEAETQELDINVATVSQAPWDDET
  PGPSYSSSEQVHVTMSSLLNTSDSSDEELVTGGATSQIQGVQTNDDLNNDSDDSSDNCVI
  VGFVKPLAERTPELVELSSDSEDLGSYEKMETVKTQEQEQSYSSGDSDVSRCSSPHSVLG
  KDEQINKGHCDSSTRIKSKKEEKRSTSLSSPRNLNSSVRGDRVYSPYNHRHRKRGRSRSS
  DSRSQSRSGHDQKNHRKHHGKKRMKSKRSRSRESSRPRGRRDKKRSRTRDSSWSRRSQTL
  SLSSESTSRSRSRSSDHGKRRSRSRNRDRYYLRNNYGSRYKWEYTYYSRNKDRDGYESSY
  RRRTLSRAHYSRQSSSPEFRVQSFSERTNARKKNNHSERKYYYYERHRSRSLSSNRSRTA
  STGTDRVRNEKPGGKRKYKTRHLEGTNEVAQPSREFASKAKDSHYQKSSSKLDGNYKNES
  DTFSDSRSSDRETKHKRRKRKTRSLSVEIVYEGKATDTTKHHKKKKKKHKKKHKKHHGDN
  ASRSPVVITIDSDSDKDSEVKEDTECDNSGPQDPLQNEFLAPSLEPFETKDVVTIEAEFG
  VLDKECDIATLSNNLNNANKTVDNIPPLAASVEQTLDVREESTFVSDLENQPSNIVSLQT
  EPSRQLPSPRTSLMSVCLGRDCDMS
• Function: Functions as an E3 ubiquitin-protein ligase and as an E3 SUMO1-protein ligase. Probable tumor suppressor involved in cell growth, cell proliferation and apoptosis that regulates p53/TP53 stability through ubiquitin-dependent degradation. May regulate chromatin modification through sumoylation of several chromatin modification-associated proteins. May be involved in DNA damage-induced cell death through IKBKE sumoylation.
• Tissue Specificity: Expressed at highest levels in testis and at lower levels in adrenal gland, bone marrow, brain, colon, heart, kidney, liver, muscle, ovary, pancreas, placenta, prostate, skeletal muscle, skin, small intestine, spleen, stomach, testis, thymus, thyroid and uterus. Expressed in the alveolar epithelium of the lung. Expression is commonly decreased in colon adenocarcinomas and lung cancers.
• Reactome Pathway:
  SUMOylation of SUMOylation proteins (R-HSA-4085377)
  SUMOylation of immune response proteins (R-HSA-4755510)
  SUMOylation of transcription cofactors (R-HSA-3899300)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Definitive	Autosomal dominant	[1]
Retinitis pigmentosa 31	DISLG2GD	Definitive	Autosomal dominant	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[6]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[7]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[8]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[9]
Lung cancer	DISCM4YA	Limited	Biomarker	[10]
Lung carcinoma	DISTR26C	Limited	Biomarker	[10]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[10]

6 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 E3 ubiquitin-protein ligase Topors (TOPORS).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase Topors (TOPORS).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase Topors (TOPORS).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of E3 ubiquitin-protein ligase Topors (TOPORS).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase Topors (TOPORS).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase Topors (TOPORS).	[17]

3 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 increases the sumoylation of E3 ubiquitin-protein ligase Topors (TOPORS).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase Topors (TOPORS).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of E3 ubiquitin-protein ligase Topors (TOPORS).	[18]

References

• [1] 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.
• [2] Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy. Am J Hum Genet. 2007 Nov;81(5):1098-103. doi: 10.1086/521953. Epub 2007 Sep 26.
• [3] Identification of prefrontal cortex protein alterations in Alzheimer's disease.Oncotarget. 2018 Jan 24;9(13):10847-10867. doi: 10.18632/oncotarget.24303. eCollection 2018 Feb 16.
• [4] Novel potential ALL low-risk markers revealed by gene expression profiling with new high-throughput SSH-CCS-PCR.Leukemia. 2003 Sep;17(9):1891-900. doi: 10.1038/sj.leu.2403073.
• [5] Integration of transcriptome and proteome profiles in glioblastoma: looking for the missing link.BMC Mol Biol. 2018 Nov 21;19(1):13. doi: 10.1186/s12867-018-0115-6.
• [6] Ubiquitination by TOPORS regulates the prostate tumor suppressor NKX3.1.J Biol Chem. 2008 Feb 22;283(8):4834-40. doi: 10.1074/jbc.M708630200. Epub 2007 Dec 12.
• [7] The E3 ligase Topors induces the accumulation of polysumoylated forms of DNA topoisomerase I in vitro and in vivo.FEBS Lett. 2007 Nov 27;581(28):5418-24. doi: 10.1016/j.febslet.2007.10.040. Epub 2007 Oct 30.
• [8] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] Expression of LUN gene that encodes a novel RING finger protein is correlated with development and progression of non-small cell lung cancer.Lung Cancer. 2004 Oct;46(1):21-8. doi: 10.1016/j.lungcan.2004.03.009.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [14] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] 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.