Details of Drug Off-Target (DOT)

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

• DOT Name: Geminin (GMNN)
• Gene Name: GMNN
• Related Disease:
  Meier-Gorlin syndrome 6
  Meier-Gorlin syndrome
• UniProt ID: GEMI_HUMAN
• PDB ID: 1T6F; 1UII; 2LP0; 2WVR; 4BRY; 7KLZ
• Pfam ID: PF07412
• Sequence:
  MNPSMKQKQEEIKENIKNSSVPRRTLKMIQPSASGSLVGRENELSAGLSKRKHRNDHLTS
  TTSSPGVIVPESSENKNLGGVTQESFDLMIKENPSSQYWKEVAEKRRKALYEALKENEKL
  HKEIEQKDNEIARLKKENKELAEVAEHVQYMAELIERLNGEPLDNFESLDNQEFDSEEET
  VEDSLVEDSEIGTCAEGTVSSSTDAKPCI
• Function: Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC). It is degraded during the mitotic phase of the cell cycle. Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle. Inhibits histone acetyltransferase activity of KAT7/HBO1 in a CDT1-dependent manner, inhibiting histone H4 acetylation and DNA replication licensing. Inhibits the transcriptional activity of a subset of Hox proteins, enrolling them in cell proliferative control.
• Reactome Pathway:
  Activation of the pre-replicative complex (R-HSA-68962)
  Switching of origins to a post-replicative state (R-HSA-69052)
  Assembly of the pre-replicative complex (R-HSA-68867)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Meier-Gorlin syndrome 6	DISXGIYN	Strong	Autosomal dominant	[1]
Meier-Gorlin syndrome	DISCFIU3	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Geminin (GMNN) affects the response to substance of Vinblastine.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Geminin (GMNN).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Geminin (GMNN).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Geminin (GMNN).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Geminin (GMNN).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Geminin (GMNN).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Geminin (GMNN).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Geminin (GMNN).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Geminin (GMNN).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Geminin (GMNN).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Geminin (GMNN).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Geminin (GMNN).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Geminin (GMNN).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Geminin (GMNN).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Geminin (GMNN).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Geminin (GMNN).	[15]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Geminin (GMNN).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Geminin (GMNN).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Geminin (GMNN).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Geminin (GMNN).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Geminin (GMNN).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Geminin (GMNN).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Geminin (GMNN).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Geminin (GMNN).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Geminin (GMNN).	[25]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Geminin (GMNN).	[26]

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 Geminin (GMNN).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Geminin (GMNN).	[20]

References

• [1] De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. Am J Hum Genet. 2015 Dec 3;97(6):904-13. doi: 10.1016/j.ajhg.2015.11.006.
• [2] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [17] Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. 2004 Jul-Aug;6(4):354-63. doi: 10.1593/neo.03478.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] 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.
• [20] 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.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [27] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.