Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEWN06R)

• DOT Name: Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1)
• Synonyms: HP1-binding protein enriched in inactive X chromosome protein 1; HBiX1; Receptor-interacting factor 1
• Gene Name: LRIF1
• Related Disease:
  Fibrosarcoma
  Facioscapulohumeral muscular dystrophy 3, digenic
• UniProt ID: LRIF1_HUMAN
• Pfam ID: PF15741
• Sequence:
  MSNNLRRVFLKPAEENSGNASRCVSGCMYQVVQTIGSDGKNLLQLLPIPKSSGNLIPLVQ
  SSVMSDALKGNTGKPVQVTFQTQISSSSTSASVQLPIFQPASSSNYFLTRTVDTSEKGRV
  TSVGTGNFSSSVSKVQSHGVKIDGLTMQTFAVPPSTQKDSSFIVVNTQSLPVTVKSPVLP
  SGHHLQIPAHAEVKSVPASSLPPSVQQKILATATTSTSGMVEASQMPTVIYVSPVNTVKN
  VVTKNFQNIYPKPVTEIAKPVILNTTQIPKNVATETQLKGGQHSQAAPVKWIFQDNLQPF
  TPSLVPVKSSNNVASKILKTFVDRKNLGDNTINMPPLSTIDPSGTRSKNMPIKDNALVMF
  NGKVYLLAKKGTDVLPSQIDQQNSVSPDTPVRKDTLQTVSSSPVTEISREVVNIVLAKSK
  SSQMETKSLSNTQLASMANLRAEKNKVEKPSPSTTNPHMNQSSNYLKQSKTLFTNPIFPV
  GFSTGHNAPRKVTAVIYARKGSVLQSIEKISSSVDATTVTSQQCVFRDQEPKIHNEMAST
  SDKGAQGRNDKKDSQGRSNKALHLKSDAEFKKIFGLTKDLRVCLTRIPDHLTSGEGFDSF
  SSLVKSGTYKETEFMVKEGERKQQNFDKKRKAKTNKKMDHIKKRKTENAYNAIINGEANV
  TGSQLLSSILPTSDVSQHNILTSHSKTRQEKRTEMEYYTHEKQEKGTLNSNAAYEQSHFF
  NKNYTEDIFPVTPPELEETIRDEKIRRLKQVLREKEAALEEMRKKMHQK
• Function: Together with SMCHD1, involved in chromosome X inactivation in females by promoting the compaction of heterochromatin. Also able to repress the ligand-induced transcriptional activity of retinoic acid receptor alpha (RARA), possibly through direct recruitment of histone deacetylases. Also required for silencing of the DUX4 locus in somatic cells.
• Tissue Specificity: Widely expressed, with the highest expression levels in heart, liver and placenta.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[1]
Facioscapulohumeral muscular dystrophy 3, digenic	DISD09NZ	Limited	Unknown	[2]

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 Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[3]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[13]

9 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 Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).	[15]

References

• [1] Mesenchymal stem cells as a gene therapy carrier for treatment of fibrosarcoma.Cytotherapy. 2009;11(5):516-26. doi: 10.1080/14653240902960429.
• [2] Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy. Neurology. 2020 Jun 9;94(23):e2441-e2447. doi: 10.1212/WNL.0000000000009617. Epub 2020 May 28.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.