Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0HP4S)

• DOT Name: RecQ-mediated genome instability protein 2 (RMI2)
• Synonyms: hRMI2; BLM-associated protein of 18 kDa; BLAP18
• Gene Name: RMI2
• Related Disease:
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Coeliac disease
  Dermatomyositis
  Multiple sclerosis
  Myotonic dystrophy type 1
  Primary biliary cholangitis
  Primary sclerosing cholangitis
  STAT3-related early-onset multisystem autoimmune disease
  Type-1 diabetes
  Type-1/2 diabetes
  Asthma
  Bloom syndrome
  Immune system disorder
  Leprosy
  Ankylosing spondylitis
  Crohn disease
  Inflammatory bowel disease
  Psoriasis
  Sclerosing cholangitis
  Ulcerative colitis
• UniProt ID: RMI2_HUMAN
• PDB ID: 3MXN; 3NBH; 4DAY
• Pfam ID: PF16100
• Sequence:
  MAAAADSFSGGPAGVRLPRSPPLKVLAEQLRRDAEGGPGAWRLSRAAAGRGPLDLAAVWM
  QGRVVMADRGEARLRDPSGDFSVRGLERVPRGRPCLVPGKYVMVMGVVQACSPEPCLQAV
  KMTDLSDNPIHESMWELEVEDLHRNIP
• Function: Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates. It is required to regulate sister chromatid segregation and to limit DNA crossover. Essential for the stability, localization, and function of BLM, TOP3A, and complexes containing BLM. In the RMI complex, it is required to target BLM to chromatin and stress-induced nuclear foci and mitotic phosphorylation of BLM.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[1]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[1]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[2]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[3]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[4]
Myotonic dystrophy type 1	DISJC0OX	Strong	Biomarker	[3]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[5]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Genetic Variation	[6]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[1]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[7]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[3]
Asthma	DISW9QNS	moderate	Genetic Variation	[8]
Bloom syndrome	DISKXQ7J	moderate	Biomarker	[9]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[10]
Leprosy	DISAA4UI	moderate	Genetic Variation	[11]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[12]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[13]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[13]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[12]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[12]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[12]

22 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 RecQ-mediated genome instability protein 2 (RMI2).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RecQ-mediated genome instability protein 2 (RMI2).	[21]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[22]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[22]
Menadione	DMSJDTY	Approved	Menadione affects the expression of RecQ-mediated genome instability protein 2 (RMI2).	[21]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[24]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[29]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[32]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of RecQ-mediated genome instability protein 2 (RMI2).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of RecQ-mediated genome instability protein 2 (RMI2).	[31]

References

• [1] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [2] Multiple common variants for celiac disease influencing immune gene expression.Nat Genet. 2010 Apr;42(4):295-302. doi: 10.1038/ng.543. Epub 2010 Feb 28.
• [3] The major dermatomyositis-specific Mi-2 autoantigen is a presumed helicase involved in transcriptional activation.Arthritis Rheum. 1995 Oct;38(10):1389-99. doi: 10.1002/art.1780381006.
• [4] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [5] Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2012 Oct;44(10):1137-41. doi: 10.1038/ng.2395. Epub 2012 Sep 9.
• [6] Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.Nat Genet. 2013 Jun;45(6):670-5. doi: 10.1038/ng.2616. Epub 2013 Apr 21.
• [7] Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.Nat Genet. 2015 Apr;47(4):381-6. doi: 10.1038/ng.3245. Epub 2015 Mar 9.
• [8] Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.Eur J Hum Genet. 2011 Apr;19(4):458-64. doi: 10.1038/ejhg.2010.191. Epub 2010 Dec 8.
• [9] Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome.PLoS Genet. 2016 Dec 15;12(12):e1006483. doi: 10.1371/journal.pgen.1006483. eCollection 2016 Dec.
• [10] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [11] Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy.Nat Genet. 2015 Mar;47(3):267-71. doi: 10.1038/ng.3212. Epub 2015 Feb 2.
• [12] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [13] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [19] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] 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.
• [22] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [23] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [26] Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands. Toxicol Lett. 2011 Oct 10;206(2):178-88.
• [27] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [30] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [31] 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.
• [32] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [33] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.