Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1A26OW)

• DOT Name: E3 ubiquitin-protein ligase TRIM7 (TRIM7)
• Synonyms: EC 2.3.2.27; Glycogenin-interacting protein; RING finger protein 90; Tripartite motif-containing protein 7
• Gene Name: TRIM7
• Related Disease:
  Hepatitis B virus infection
  Neoplasm
  Hepatocellular carcinoma
• UniProt ID: TRIM7_HUMAN
• PDB ID: 6UMA; 6UMB; 7OVX; 7OW2; 7W0Q; 7W0S; 7W0T; 7X6Y; 7X6Z; 7X70; 7Y3A; 7Y3B; 7Y3C; 8A5L; 8A5M; 8A8X
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF15227
• Sequence:
  MAAVGPRTGPGTGAEALALAAELQGEATCSICLELFREPVSVECGHSFCRACIGRCWERP
  GAGSVGAATRAPPFPLPCPQCREPARPSQLRPNRQLAAVATLLRRFSLPAAAPGEHGSQA
  AAARAAAARCGQHGEPFKLYCQDDGRAICVVCDRAREHREHAVLPLDEAVQEAKELLESR
  LRVLKKELEDCEVFRSTEKKESKELLKQMAAEQEKVGAEFQALRAFLVEQEGRLLGRLEE
  LSREVAQKQNENLAQLGVEITQLSKLSSQIQETAQKPDLDFLQEFKSTLSRCSNVPGPKP
  TTVSSEMKNKVWNVSLKTFVLKGMLKKFKEDLRGELEKEEKVELTLDPDTANPRLILSLD
  LKGVRLGERAQDLPNHPCRFDTNTRVLASCGFSSGRHHWEVEVGSKDGWAFGVARESVRR
  KGLTPFTPEEGVWALQLNGGQYWAVTSPERSPLSCGHLSRVRVALDLEVGAVSFYAVEDM
  RHLYTFRVNFQERVFPLFSVCSTGTYLRIWP
• Function: E3 ubiquitin-protein ligase that have both tumor-promoting and tumor-suppressing activities and functions in several biological processes including innate immunity, regulation of ferroptosis as well as cell proliferation and migration. Acts as an antiviral effector against multiple viruses by targeting specific viral proteins for ubiquitination and degradation including norovirus NTPase protein or SARS-CoV-2 NSP5 and NSP8 proteins. Mechanistically, recognizes the C-terminal glutamine-containing motif usually generated by viral proteases that process the polyproteins and trigger their ubiquitination and subsequent degradation. Mediates 'Lys-63'-linked polyubiquitination and stabilization of the JUN coactivator RNF187 in response to growth factor signaling via the MEK/ERK pathway, thereby regulating JUN transactivation and cellular proliferation. Promotes the TLR4-mediated signaling activation through its E3 ligase domain leading to production of pro-inflammatory cytokines and type I interferon. Also plays a negative role in the regulation of exogenous cytosolic DNA virus-triggered immune response. Mechanistically, enhances the 'Lys-48'-linked ubiquitination of STING1 leading to its proteasome-dependent degradation. Mediates the ubiquitination of the SIN3-HDAC chromatin remodeling complex component BRMS1. Modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells by ubiquitinating NCOA4, leading to its degradation ; (Microbial infection) Promotes Zika virus replication by mediating envelope protein E ubiquitination.
• Tissue Specificity: Skeletal muscle and placenta, at lower levels in heart, brain and pancreas. Isoform 1 is widely expressed with high level in testis, kidney and heart.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase TRIM7 (TRIM7).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase TRIM7 (TRIM7).	[4]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin-protein ligase TRIM7 (TRIM7).	[5]

1 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 decreases the methylation of E3 ubiquitin-protein ligase TRIM7 (TRIM7).	[6]

References

• [1] Tripartite motif-containing protein 7 regulates hepatocellular carcinoma cell proliferation via the DUSP6/p38 pathway.Biochem Biophys Res Commun. 2019 Apr 16;511(4):889-895. doi: 10.1016/j.bbrc.2019.02.001. Epub 2019 Mar 5.
• [2] The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein.Cell Death Differ. 2020 Jun;27(6):1819-1831. doi: 10.1038/s41418-019-0464-9. Epub 2019 Dec 4.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [5] 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.
• [6] 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.