Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCU6CYA)

• DOT Name: Roquin-1 (RC3H1)
• Synonyms: Roquin; EC 2.3.2.27; RING finger and C3H zinc finger protein 1; RING finger and CCCH-type zinc finger domain-containing protein 1; RING finger protein 198
• Gene Name: RC3H1
• Related Disease:
  Adult lymphoma
  Angioimmunoblastic T-cell Lymphoma
  Lymphoma
  Neoplasm
  Pediatric lymphoma
  Intestinal disorder
  Systemic lupus erythematosus
  Autoimmune disease
  Hemophagocytic lymphohistiocytosis, familial, 6
• UniProt ID: RC3H1_HUMAN
• PDB ID: 3X1O; 4QIK; 4QIL; 4ULW; 4YWQ
• EC Number: 2.3.2.27
• Pfam ID: PF18386 ; PF21206 ; PF14634
• Sequence:
  MPVQAPQWTDFLSCPICTQTFDETIRKPISLGCGHTVCKMCLNKLHRKACPFDQTTINTD
  IELLPVNSALLQLVGAQVPEQQPITLCSGVEDTKHYEEAKKCVEELALYLKPLSSARGVG
  LNSTTQSVLSRPMQRKLVTLVHCQLVEEEGRIRAMRAARSLGERTVTELILQHQNPQQLS
  SNLWAAVRARGCQFLGPAMQEEALKLVLLALEDGSALSRKVLVLFVVQRLEPRFPQASKT
  SIGHVVQLLYRASCFKVTKRDEDSSLMQLKEEFRTYEALRREHDSQIVQIAMEAGLRIAP
  DQWSSLLYGDQSHKSHMQSIIDKLQTPASFAQSVQELTIALQRTGDPANLNRLRPHLELL
  ANIDPSPDAPPPTWEQLENGLVAVRTVVHGLVDYIQNHSKKGADQQQPPQHSKYKTYMCR
  DMKQRGGCPRGASCTFAHSQEELEKFRKMNKRLVPRRPLSASLGQLNEVGLPSAAILPDE
  GAVDLPSRKPPALPNGIVSTGNTVTQLIPRGTDPSYDSSLKPGKIDHLSSSAPGSPPDLL
  ESVPKSISALPVNPHSIPPRGPADLPPMPVTKPLQMVPRGSQLYPAQQTDVYYQDPRGAA
  PPFEPAPYQQGMYYTPPPQCVSRFVRPPPSAPEPAPPYLDHYPPYLQERVVNSQYGTQPQ
  QYPPIYPSHYDGRRVYPAPSYTREEIFRESPIPIEIPPAAVPSYVPESRERYQQIESYYP
  VAPHPTQIRPSYLREPPYSRLPPPPQPHPSLDELHRRRKEIMAQLEERKVISPPPFAPSP
  TLPPTFHPEEFLDEDLKVAGKYKGNDYSQYSPWSCDTIGSYIGTKDAKPKDVVAAGSVEM
  MNVESKGMRDQRLDLQRRAAETSDDDLIPFGDRPTVSRFGAISRTSKTIYQGAGPMQAMA
  PQGAPTKSINISDYSPYGTHGGWGASPYSPHQNIPSQGHFSERERISMSEVASHGKPLPS
  AEREQLRLELQQLNHQISQQTQLRGLEAVSNRLVLQREANTLAGQSQPPPPPPPKWPGMI
  SSEQLSLELHQVEREIGKRTRELSMENQCSLDMKSKLNTSKQAENGQPEPQNKVPAEDLT
  LTFSDVPNGSALTQENISLLSNKTSSLNLSEDPEGGGDNNDSQRSGVTPSSAP
• Function: Post-transcriptional repressor of mRNAs containing a conserved stem loop motif, called constitutive decay element (CDE), which is often located in the 3'-UTR, as in HMGXB3, ICOS, IER3, NFKBID, NFKBIZ, PPP1R10, TNF, TNFRSF4 and in many more mRNAs. Cleaves translationally inactive mRNAs harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-independent manner. Binds to CDE and promotes mRNA deadenylation and degradation. This process does not involve miRNAs. In follicular helper T (Tfh) cells, represses of ICOS and TNFRSF4 expression, thus preventing spontaneous Tfh cell differentiation, germinal center B-cell differentiation in the absence of immunization and autoimmunity. In resting or LPS-stimulated macrophages, controls inflammation by suppressing TNF expression. Also recognizes CDE in its own mRNA and in that of paralogous RC3H2, possibly leading to feedback loop regulation. Recognizes and binds mRNAs containing a hexaloop stem-loop motif, called alternative decay element (ADE). Together with ZC3H12A, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR. Able to interact with double-stranded RNA (dsRNA). miRNA-binding protein that regulates microRNA homeostasis. Enhances DICER-mediated processing of pre-MIR146a but reduces mature MIR146a levels through an increase of 3' end uridylation. Both inhibits ICOS mRNA expression and they may act together to exert the suppression. Acts as a ubiquitin E3 ligase. Pairs with E2 enzymes UBE2A, UBE2B, UBE2D2, UBE2F, UBE2G1, UBE2G2 and UBE2L3 and produces polyubiquitin chains. Shows the strongest activity when paired with UBE2N:UBE2V1 or UBE2N:UBE2V2 E2 complexes and generate both short and long polyubiquitin chains.
• Tissue Specificity: Widely expressed. Expressed at higher level in cerebellum, spleen, ovary and liver.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Definitive	Biomarker	[1]
Angioimmunoblastic T-cell Lymphoma	DISZPFTL	Definitive	Altered Expression	[2]
Lymphoma	DISN6V4S	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[2]
Pediatric lymphoma	DIS51BK2	Definitive	Biomarker	[1]
Intestinal disorder	DISGPMUQ	Strong	Altered Expression	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Limited	Altered Expression	[3]
Hemophagocytic lymphohistiocytosis, familial, 6	DISSDZPD	Limited	Unknown	[5]

12 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 Roquin-1 (RC3H1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Roquin-1 (RC3H1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Roquin-1 (RC3H1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Roquin-1 (RC3H1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Roquin-1 (RC3H1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Roquin-1 (RC3H1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Roquin-1 (RC3H1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Roquin-1 (RC3H1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Roquin-1 (RC3H1).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Roquin-1 (RC3H1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Roquin-1 (RC3H1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Roquin-1 (RC3H1).	[18]

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 affects the phosphorylation of Roquin-1 (RC3H1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Roquin-1 (RC3H1).	[17]

References

• [1] T-cell regulation by casitas B-lineage lymphoma (Cblb) is a critical failsafe against autoimmune disease due to autoimmune regulator (Aire) deficiency.Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14709-14. doi: 10.1073/pnas.1009209107. Epub 2010 Jul 28.
• [2] ROQUIN/RC3H1 alterations are not found in angioimmunoblastic T-cell lymphoma.PLoS One. 2013 Jun 25;8(6):e64536. doi: 10.1371/journal.pone.0064536. Print 2013.
• [3] ROQUIN signalling pathways in innate and adaptive immunity.Eur J Immunol. 2016 May;46(5):1082-90. doi: 10.1002/eji.201545956. Epub 2016 Apr 23.
• [4] Roquin--a multifunctional regulator of immune homeostasis.Genes Immun. 2016 Mar;17(2):79-84. doi: 10.1038/gene.2015.58. Epub 2015 Dec 17.
• [5] A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature. 2005 May 26;435(7041):452-8. doi: 10.1038/nature03555.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] 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.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.