Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGAMLM4)

• DOT Name: FAS-associated factor 1 (FAF1)
• Synonyms: hFAF1; UBX domain-containing protein 12; UBX domain-containing protein 3A
• Gene Name: FAF1
• UniProt ID: FAF1_HUMAN
• PDB ID: 1H8C; 2DZM; 2EC4; 3E21; 3QC8; 3QCA; 3QQ8; 3QWZ; 3QX1; 3R3M; 7FGM; 7FGN
• Pfam ID: PF21021 ; PF14555 ; PF00789
• Sequence:
  MASNMDREMILADFQACTGIENIDEAITLLEQNNWDLVAAINGVIPQENGILQSEYGGET
  IPGPAFNPASHPASAPTSSSSSAFRPVMPSRQIVERQPRMLDFRVEYRDRNVDVVLEDTC
  TVGEIKQILENELQIPVSKMLLKGWKTGDVEDSTVLKSLHLPKNNSLYVLTPDLPPPSSS
  SHAGALQESLNQNFMLIITHREVQREYNLNFSGSSTIQEVKRNVYDLTSIPVRHQLWEGW
  PTSATDDSMCLAESGLSYPCHRLTVGRRSSPAQTREQSEEQITDVHMVSDSDGDDFEDAT
  EFGVDDGEVFGMASSALRKSPMMPENAENEGDALLQFTAEFSSRYGDCHPVFFIGSLEAA
  FQEAFYVKARDRKLLAIYLHHDESVLTNVFCSQMLCAESIVSYLSQNFITWAWDLTKDSN
  RARFLTMCNRHFGSVVAQTIRTQKTDQFPLFLIIMGKRSSNEVLNVIQGNTTVDELMMRL
  MAAMEIFTAQQQEDIKDEDEREARENVKREQDEAYRLSLEADRAKREAHEREMAEQFRLE
  QIRKEQEEEREAIRLSLEQALPPEPKEENAEPVSKLRIRTPSGEFLERRFLASNKLQIVF
  DFVASKGFPWDEYKLLSTFPRRDVTQLDPNKSLLEVKLFPQETLFLEAKE
• Function: Ubiquitin-binding protein. Required for the progression of DNA replication forks by targeting DNA replication licensing factor CDT1 for degradation. Potentiates but cannot initiate FAS-induced apoptosis.
• Tissue Specificity: Most abundant in testis, slightly less abundant in skeletal muscle and heart, followed by prostate, thymus, ovary, small intestine, and colon. Not detected in the peripheral blood leukocytes.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of FAS-associated factor 1 (FAF1).	[1]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of FAS-associated factor 1 (FAF1).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of FAS-associated factor 1 (FAF1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of FAS-associated factor 1 (FAF1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of FAS-associated factor 1 (FAF1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of FAS-associated factor 1 (FAF1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of FAS-associated factor 1 (FAF1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of FAS-associated factor 1 (FAF1).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of FAS-associated factor 1 (FAF1).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of FAS-associated factor 1 (FAF1).	[8]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of FAS-associated factor 1 (FAF1).	[9]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of FAS-associated factor 1 (FAF1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of FAS-associated factor 1 (FAF1).	[11]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of FAS-associated factor 1 (FAF1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of FAS-associated factor 1 (FAF1).	[13]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] 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.
• [4] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [5] 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.
• [6] 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.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [8] Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells. Br J Cancer. 2007 Oct 22;97(8):1099-105. doi: 10.1038/sj.bjc.6604003. Epub 2007 Sep 25.
• [9] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [10] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] 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.
• [15] 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.