Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase RLIM (RLIM)
• Synonyms: EC 2.3.2.27; LIM domain-interacting RING finger protein; RING finger LIM domain-binding protein; R-LIM; RING finger protein 12; RING-type E3 ubiquitin transferase RLIM; Renal carcinoma antigen NY-REN-43
• Gene Name: RLIM
• Related Disease:
  Non-syndromic X-linked intellectual disability
  Autism
  Intellectual disability, autosomal dominant 40
  Intellectual disability, X-linked 61
  Prostate cancer
  Prostate neoplasm
  Hepatocellular carcinoma
  Syndromic intellectual disability
  Lung cancer
  Lung carcinoma
  Intellectual disability
• UniProt ID: RNF12_HUMAN
• PDB ID: 6W7Z; 6W9A; 6W9D
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MENSDSNDKGSGDQSAAQRRSQMDRLDREEAFYQFVNNLSEEDYRLMRDNNLLGTPGEST
  EEELLRRLQQIKEGPPPQNSDENRGGDSSDDVSNGDSIIDWLNSVRQTGNTTRSGQRGNQ
  SWRAVSRTNPNSGDFRFSLEINVNRNNGSQNSENENEPSARRSSGENVENNSQRQVENPR
  SESTSARPSRSERNSTEALTEVPPTRGQRRARSRSPDHRRTRARAERSRSPLHPMSEIPR
  RSHHSISSQTFEHPLVNETEGSSRTRHHVTLRQQISGPELLSRGLFAASGTRNASQGAGS
  SDTAASGESTGSGQRPPTIVLDLQVRRVRPGEYRQRDSIASRTRSRSQTPNNTVTYESER
  GGFRRTFSRSERAGVRTYVSTIRIPIRRILNTGLSETTSVAIQTMLRQIMTGFGELSYFM
  YSDSDSEPTGSVSNRNMERAESRSGRGGSGGGSSSGSSSSSSSSSSSSSSSSSSSSPSSS
  SGGESSETSSDLFEGSNEGSSSSGSSGARREGRHRAPVTFDESGSLPFLSLAQFFLLNED
  DDDQPRGLTKEQIDNLAMRSFGENDALKTCSVCITEYTEGNKLRKLPCSHEYHVHCIDRW
  LSENSTCPICRRAVLASGNRESVV
• Function: E3 ubiquitin-protein ligase. Acts as a negative coregulator for LIM homeodomain transcription factors by mediating the ubiquitination and subsequent degradation of LIM cofactors LDB1 and LDB2 and by mediating the recruitment the SIN3a/histone deacetylase corepressor complex. Ubiquitination and degradation of LIM cofactors LDB1 and LDB2 allows DNA-bound LIM homeodomain transcription factors to interact with other protein partners such as RLIM. Plays a role in telomere length-mediated growth suppression by mediating the ubiquitination and degradation of TERF1. By targeting ZFP42 for degradation, acts as an activator of random inactivation of X chromosome in the embryo, a stochastic process in which one X chromosome is inactivated to minimize sex-related dosage differences of X-encoded genes in somatic cells of female placental mammals.
• Tissue Specificity: Expressed in many tissues.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-syndromic X-linked intellectual disability	DIS71AI3	Definitive	X-linked	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[1]
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	X-linked recessive	[2]
Intellectual disability, X-linked 61	DISGU0ZU	Strong	X-linked	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[4]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[2]
Lung cancer	DISCM4YA	Disputed	Biomarker	[5]
Lung carcinoma	DISTR26C	Disputed	Biomarker	[5]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[6]

10 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 E3 ubiquitin-protein ligase RLIM (RLIM).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[15]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of E3 ubiquitin-protein ligase RLIM (RLIM).	[16]

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 affects the methylation of E3 ubiquitin-protein ligase RLIM (RLIM).	[12]

References

• [1] Syndromic X-linked intellectual disability segregating with a missense variant in RLIM. Eur J Hum Genet. 2015 Dec;23(12):1652-6. doi: 10.1038/ejhg.2015.30. Epub 2015 Mar 4.
• [2] X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.
• [3] Microarray comparison of prostate tumor gene expression in African-American and Caucasian American males: a pilot project study.Infect Agent Cancer. 2009 Feb 10;4 Suppl 1(Suppl 1):S3. doi: 10.1186/1750-9378-4-S1-S3.
• [4] RLIM suppresses hepatocellular carcinogenesis by up-regulating p15 and p21.Oncotarget. 2017 Sep 15;8(47):83075-83087. doi: 10.18632/oncotarget.20904. eCollection 2017 Oct 10.
• [5] TGF-Induced Lung Cancer Cell Migration Is NR4A1-Dependent.Mol Cancer Res. 2018 Dec;16(12):1991-2002. doi: 10.1158/1541-7786.MCR-18-0366. Epub 2018 Aug 2.
• [6] Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder. Mol Psychiatry. 2019 Nov;24(11):1748-1768. doi: 10.1038/s41380-018-0065-x. Epub 2018 May 4.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.