Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ZVTFL)

• DOT Name: RecQ-mediated genome instability protein 1 (RMI1)
• Synonyms: BLM-associated protein of 75 kDa; BLAP75; FAAP75
• Gene Name: RMI1
• Related Disease:
  Neoplasm
  Acute myelogenous leukaemia
  Advanced cancer
  Epithelial ovarian cancer
  Melanoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Isolated congenital microcephaly
  Colorectal carcinoma
• UniProt ID: RMI1_HUMAN
• PDB ID: 3MXN; 3NBH; 3NBI; 4CGY; 4CHT; 4DAY; 7XUV
• Pfam ID: PF16099 ; PF08585 ; PF21000
• Sequence:
  MNVTSIALRAETWLLAAWHVKVPPMWLEACINWIQEENNNVNLSQAQMNKQVFEQWLLTD
  LRDLEHPLLPDGILEIPKGELNGFYALQINSLVDVSQPAYSQIQKLRGKNTTNDLVTAEA
  QVTPKPWEAKPSRMLMLQLTDGIVQIQGMEYQPIPILHSDLPPGTKILIYGNISFRLGVL
  LLKPENVKVLGGEVDALLEEYAQEKVLARLIGEPDLVVSVIPNNSNENIPRVTDVLDPAL
  GPSDEELLASLDENDELTANNDTSSERCFTTGSSSNTIPTRQSSFEPEFVISPRPKEEPS
  NLSIHVMDGELDDFSLEEALLLEETVQKEQMETKELQPLTFNRNADRSIERFSHNPNTTN
  NFSLTCKNGNNNWSEKNVSEQMTNEDKSFGCPSVRDQNRSIFSVHCNVPLAHDFTNKEKN
  LETDNKIKQTSSSDSHSLNNKILNREVVNYVQKRNSQISNENDCNLQSCSLRSSENSINL
  SIAMDLYSPPFVYLSVLMASKPKEVTTVKVKAFIVTLTGNLSSSGGIWSITAKVSDGTAY
  LDVDFVDEILTSLIGFSVPEMKQSKKDPLQYQKFLEGLQKCQRDLIDLCCLMTISFNPSL
  SKAMVLALQDVNMEHLENLKKRLNK
• Function: Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates to limit DNA crossover formation in cells. Promotes TOP3A binding to double Holliday junctions (DHJ) and hence stimulates TOP3A-mediated dissolution. Required for BLM phosphorylation during mitosis. Within the BLM complex, required for BLM and TOP3A stability.
• 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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[4]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[4]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[6]

12 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 1 (RMI1).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[17]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of RecQ-mediated genome instability protein 1 (RMI1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RecQ-mediated genome instability protein 1 (RMI1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of RecQ-mediated genome instability protein 1 (RMI1).	[14]

References

• [1] RMI1 attenuates tumor development and is essential for early embryonic survival.Mol Carcinog. 2011 Feb;50(2):80-8. doi: 10.1002/mc.20694. Epub 2010 Nov 23.
• [2] Genetic variant of the human homologous recombination-associated gene RMI1 (S455N) impacts the risk of AML/MDS and malignant melanoma.Cancer Lett. 2007 Dec 8;258(1):38-44. doi: 10.1016/j.canlet.2007.08.005. Epub 2007 Sep 27.
• [3] Risk of Ovarian Malignancy Algorithm versus Risk Malignancy Index-I for Preoperative Assessment of Adnexal Masses: A Systematic Review and Meta-Analysis.Gynecol Obstet Invest. 2019;84(6):591-598. doi: 10.1159/000501681. Epub 2019 Jul 16.
• [4] Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes.Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):3030-5. doi: 10.1158/1055-9965.EPI-09-0772. Epub 2009 Oct 27.
• [5] Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.Am J Hum Genet. 2018 Aug 2;103(2):221-231. doi: 10.1016/j.ajhg.2018.07.001. Epub 2018 Jul 26.
• [6] Colorectal cancer and polymorphisms in DNA repair genes WRN, RMI1 and BLM.Carcinogenesis. 2010 Mar;31(3):442-5. doi: 10.1093/carcin/bgp293. Epub 2009 Nov 27.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [18] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.