Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH8UB6H)

• DOT Name: E3 ubiquitin-protein ligase TRIM71 (TRIM71)
• Synonyms: EC 2.3.2.27; Protein lin-41 homolog; RING-type E3 ubiquitin transferase TRIM71; Tripartite motif-containing protein 71
• Gene Name: TRIM71
• Related Disease:
  Advanced cancer
  Hydrocephalus, congenital communicating, 1
  Neoplasm
  Hepatocellular carcinoma
  Congenital hydrocephalus
• UniProt ID: LIN41_HUMAN
• PDB ID: 7QRX
• EC Number: 2.3.2.27
• Pfam ID: PF00630 ; PF01436 ; PF00643 ; PF00097
• Sequence:
  MASFPETDFQICLLCKEMCGSPAPLSSNSSASSSSSQTSTSSGGGGGGPGAAARRLHVLP
  CLHAFCRPCLEAHRLPAAGGGAAGEPLKLRCPVCDQKVVLAEAAGMDALPSSAFLLSNLL
  DAVVATADEPPPKNGRAGAPAGAGGHSNHRHHAHHAHPRASASAPPLPQAPQPPAPSRSA
  PGGPAASPSALLLRRPHGCSSCDEGNAASSRCLDCQEHLCDNCVRAHQRVRLTKDHYIER
  GPPGPGAAAAAQQLGLGPPFPGPPFSILSVFPERLGFCQHHDDEVLHLYCDTCSVPICRE
  CTMGRHGGHSFIYLQEALQDSRALTIQLLADAQQGRQAIQLSIEQAQTVAEQVEMKAKVV
  QSEVKAVTARHKKALEERECELLWKVEKIRQVKAKSLYLQVEKLRQNLNKLESTISAVQQ
  VLEEGRALDILLARDRMLAQVQELKTVRSLLQPQEDDRVMFTPPDQALYLAIKSFGFVSS
  GAFAPLTKATGDGLKRALQGKVASFTVIGYDHDGEPRLSGGDLMSAVVLGPDGNLFGAEV
  SDQQNGTYVVSYRPQLEGEHLVSVTLCNQHIENSPFKVVVKSGRSYVGIGLPGLSFGSEG
  DSDGKLCRPWGVSVDKEGYIIVADRSNNRIQVFKPCGAFHHKFGTLGSRPGQFDRPAGVA
  CDASRRIVVADKDNHRIQIFTFEGQFLLKFGEKGTKNGQFNYPWDVAVNSEGKILVSDTR
  NHRIQLFGPDGVFLNKYGFEGALWKHFDSPRGVAFNHEGHLVVTDFNNHRLLVIHPDCQS
  ARFLGSEGTGNGQFLRPQGVAVDQEGRIIVADSRNHRVQMFESNGSFLCKFGAQGSGFGQ
  MDRPSGIAITPDGMIVVVDFGNNRILVF
• Function: E3 ubiquitin-protein ligase that cooperates with the microRNAs (miRNAs) machinery and promotes embryonic stem cells proliferation and maintenance (Probable). Binds to miRNAs and associates with AGO2, participating in post-transcriptional repression of transcripts such as CDKN1A. In addition, participates in post-transcriptional mRNA repression in a miRNA independent mechanism. Facilitates the G1-S transition to promote rapid embryonic stem cell self-renewal by repressing CDKN1A expression. Required to maintain proliferation and prevent premature differentiation of neural progenitor cells during early neural development: positively regulates FGF signaling by controlling the stability of SHCBP1. Specific regulator of miRNA biogenesis. Binds to miRNA MIR29A hairpin and postranscriptionally modulates MIR29A levels, which indirectly regulates TET proteins expression.
• Tissue Specificity: Specifically expressed in testis.
• KEGG Pathway: MicroR.s in cancer (hsa05206)
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Hydrocephalus, congenital communicating, 1	DISDIJ5P	Strong	Autosomal dominant	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[3]
Congenital hydrocephalus	DIS7O6UL	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of E3 ubiquitin-protein ligase TRIM71 (TRIM71).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase TRIM71 (TRIM71).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase TRIM71 (TRIM71).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM71 (TRIM71).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase TRIM71 (TRIM71).	[8]

References

• [1] TRIM71 suppresses tumorigenesis via modulation of Lin28B-let-7-HMGA2 signaling.Oncotarget. 2016 Nov 29;7(48):79854-79868. doi: 10.18632/oncotarget.13036.
• [2] The let-7 microRNA target gene, Mlin41/Trim71 is required for mouse embryonic survival and neural tube closure. Cell Cycle. 2008 Dec 15;7(24):3935-42. doi: 10.4161/cc.7.24.7397. Epub 2008 Dec 13.
• [3] The mRNA repressor TRIM71 cooperates with Nonsense-Mediated Decay factors to destabilize the mRNA of CDKN1A/p21.Nucleic Acids Res. 2019 Dec 16;47(22):11861-11879. doi: 10.1093/nar/gkz1057.
• [4] Trim71/lin-41 Links an Ancient miRNA Pathway to Human Congenital Hydrocephalus.Trends Mol Med. 2019 Jun;25(6):467-469. doi: 10.1016/j.molmed.2019.03.004. Epub 2019 Apr 8.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] 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.
• [9] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.