Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZR3GF6)

• DOT Name: Roquin-2 (RC3H2)
• Synonyms: EC 2.3.2.27; Membrane-associated nucleic acid-binding protein; RING finger and CCCH-type zinc finger domain-containing protein 2; RING finger protein 164; RING-type E3 ubiquitin transferase Roquin-2
• Gene Name: RC3H2
• UniProt ID: RC3H2_HUMAN
• PDB ID: 4Z30; 4Z31; 4ZLC; 4ZLD
• EC Number: 2.3.2.27
• Pfam ID: PF18386 ; PF21206 ; PF00642 ; PF14634
• Sequence:
  MPVQAAQWTEFLSCPICYNEFDENVHKPISLGCSHTVCKTCLNKLHRKACPFDQTAINTD
  IDVLPVNFALLQLVGAQVPDHQSIKLSNLGENKHYEVAKKCVEDLALYLKPLSGGKGVAS
  LNQSALSRPMQRKLVTLVNCQLVEEEGRVRAMRAARSLGERTVTELILQHQNPQQLSANL
  WAAVRARGCQFLGPAMQEEALKLVLLALEDGSALSRKVLVLFVVQRLEPRFPQASKTSIG
  HVVQLLYRASCFKVTKRDEDSSLMQLKEEFRSYEALRREHDAQIVHIAMEAGLRISPEQW
  SSLLYGDLAHKSHMQSIIDKLQSPESFAKSVQELTIVLQRTGDPANLNRLRPHLELLANI
  DPNPDAVSPTWEQLENAMVAVKTVVHGLVDFIQNYSRKGHETPQPQPNSKYKTSMCRDLR
  QQGGCPRGTNCTFAHSQEELEKYRLRNKKINATVRTFPLLNKVGVNNTVTTTAGNVISVI
  GSTETTGKIVPSTNGISNAENSVSQLISRSTDSTLRALETVKKVGKVGANGQNAAGPSAD
  SVTENKIGSPPKTPVSNVAATSAGPSNVGTELNSVPQKSSPFLTRVPVYPPHSENIQYFQ
  DPRTQIPFEVPQYPQTGYYPPPPTVPAGVAPCVPRFVRSNNVPESSLPPASMPYADHYST
  FSPRDRMNSSPYQPPPPQPYGPVPPVPSGMYAPVYDSRRIWRPPMYQRDDIIRSNSLPPM
  DVMHSSVYQTSLRERYNSLDGYYSVACQPPSEPRTTVPLPREPCGHLKTSCEEQIRRKPD
  QWAQYHTQKAPLVSSTLPVATQSPTPPSPLFSVDFRADFSESVSGTKFEEDHLSHYSPWS
  CGTIGSCINAIDSEPKDVIANSNAVLMDLDSGDVKRRVHLFETQRRTKEEDPIIPFSDGP
  IISKWGAISRSSRTGYHTTDPVQATASQGSATKPISVSDYVPYVNAVDSRWSSYGNEATS
  SAHYVERDRFIVTDLSGHRKHSSTGDLLSLELQQAKSNSLLLQREANALAMQQKWNSLDE
  GRHLTLNLLSKEIELRNGELQSDYTEDATDTKPDRDIELELSALDTDEPDGQSEPIEEIL
  DIQLGISSQNDQLLNGMAVENGHPVQQHQKEPPKQKKQSLGEDHVILEEQKTILPVTSCF
  SQPLPVSISNASCLPITTSVSAGNLILKTHVMSEDKNDFLKPVANGKMVNS
• 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 and in many more mRNAs. 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 RC3H1, possibly leading to feedback loop regulation. 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 UBE2B, UBE2D2, UBE2E2, UBE2E3, UBE2G2, UBE2K and UBE2Q2 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. Involved in the ubiquitination of MAP3K5. Able to interact with double-stranded RNA (dsRNA).
• Tissue Specificity: Expressed in spleen, testis, ovary and small intestine.

Molecular Interaction Atlas (MIA) of This DOT

8 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-2 (RC3H2).	[1]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Roquin-2 (RC3H2).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Roquin-2 (RC3H2).	[3]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Roquin-2 (RC3H2).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Roquin-2 (RC3H2).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Roquin-2 (RC3H2).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Roquin-2 (RC3H2).	[1]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Roquin-2 (RC3H2).	[8]

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-2 (RC3H2).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Roquin-2 (RC3H2).	[7]

References

• [1] 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.
• [2] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [3] 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.
• [4] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] 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.
• [7] 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.
• [8] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.