Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1XFQXF)

• DOT Name: Flap endonuclease GEN homolog 1 (GEN1)
• Synonyms: EC 3.1.-.-
• Gene Name: GEN1
• Related Disease:
  Bilateral renal agenesis
  Renal agenesis
  Renal hypodysplasia/aplasia 1
  Vesicoureteral reflux
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Cognitive impairment
  Colorectal carcinoma
  Epithelial ovarian cancer
  Familial adenomatous polyposis
  Genital herpes
  leukaemia
  Moyamoya disease
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Vascular disease
  Advanced cancer
  Intellectual disability, autosomal recessive 1
  Methicillin-resistant staphylococci infection
  Congenital anomaly of kidney and urinary tract
  Hereditary breast carcinoma
  Familial ovarian cancer
• UniProt ID: GEN_HUMAN
• PDB ID: 5T9J
• EC Number: 3.1.-.-
• Pfam ID: PF18704 ; PF00867 ; PF00752
• Sequence:
  MGVNDLWQILEPVKQHIPLRNLGGKTIAVDLSLWVCEAQTVKKMMGSVMKPHLRNLFFRI
  SYLTQMDVKLVFVMEGEPPKLKADVISKRNQSRYGSSGKSWSQKTGRSHFKSVLRECLHM
  LECLGIPWVQAAGEAEAMCAYLNAGGHVDGCLTNDGDTFLYGAQTVYRNFTMNTKDPHVD
  CYTMSSIKSKLGLDRDALVGLAILLGCDYLPKGVPGVGKEQALKLIQILKGQSLLQRFNR
  WNETSCNSSPQLLVTKKLAHCSVCSHPGSPKDHERNGCRLCKSDKYCEPHDYEYCCPCEW
  HRTEHDRQLSEVENNIKKKACCCEGFPFHEVIQEFLLNKDKLVKVIRYQRPDLLLFQRFT
  LEKMEWPNHYACEKLLVLLTHYDMIERKLGSRNSNQLQPIRIVKTRIRNGVHCFEIEWEK
  PEHYAMEDKQHGEFALLTIEEESLFEAAYPEIVAVYQKQKLEIKGKKQKRIKPKENNLPE
  PDEVMSFQSHMTLKPTCEIFHKQNSKLNSGISPDPTLPQESISASLNSLLLPKNTPCLNA
  QEQFMSSLRPLAIQQIKAVSKSLISESSQPNTSSHNISVIADLHLSTIDWEGTSFSNSPA
  IQRNTFSHDLKSEVESELSAIPDGFENIPEQLSCESERYTANIKKVLDEDSDGISPEEHL
  LSGITDLCLQDLPLKERIFTKLSYPQDNLQPDVNLKTLSILSVKESCIANSGSDCTSHLS
  KDLPGIPLQNESRDSKILKGDQLLQEDYKVNTSVPYSVSNTVVKTCNVRPPNTALDHSRK
  VDMQTTRKILMKKSVCLDRHSSDEQSAPVFGKAKYTTQRMKHSSQKHNSSHFKESGHNKL
  SSPKIHIKETEQCVRSYETAENEESCFPDSTKSSLSSLQCHKKENNSGTCLDSPLPLRQR
  LKLRFQST
• Function: Endonuclease which resolves Holliday junctions (HJs) by the introduction of symmetrically related cuts across the junction point, to produce nicked duplex products in which the nicks can be readily ligated. Four-way DNA intermediates, also known as Holliday junctions, are formed during homologous recombination and DNA repair, and their resolution is necessary for proper chromosome segregation. Cleaves HJs by a nick and counter-nick mechanism involving dual coordinated incisions that lead to the formation of ligatable nicked duplex products. Cleavage of the first strand is rate limiting, while second strand cleavage is rapid. Largely monomeric, dimerizes on the HJ and the first nick occurs upon dimerization at the junction. Efficiently cleaves both single and double HJs contained within large recombination intermediates. Exhibits a weak sequence preference for incision between two G residues that reside in a T-rich region of DNA. Has also endonuclease activity on 5'-flap and replication fork (RF) DNA substrates.
• Reactome Pathway: Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bilateral renal agenesis	DISOR5IA	Definitive	Genetic Variation	[1]
Renal agenesis	DIS0M9AF	Definitive	Genetic Variation	[1]
Renal hypodysplasia/aplasia 1	DISOH8XN	Definitive	Genetic Variation	[1]
Vesicoureteral reflux	DISUL6SA	Definitive	Genetic Variation	[1]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[5]
Genital herpes	DISAP666	Strong	Biomarker	[7]
leukaemia	DISS7D1V	Strong	Biomarker	[8]
Moyamoya disease	DISO62CA	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Vascular disease	DISVS67S	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[11]
Intellectual disability, autosomal recessive 1	DISINB3A	moderate	Genetic Variation	[12]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[13]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Limited	Biomarker	[14]
Hereditary breast carcinoma	DISAEZT5	Refuted	Autosomal dominant	[15]
Familial ovarian cancer	DISGLR2C	No Known	Autosomal dominant	[15]

1 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 Flap endonuclease GEN homolog 1 (GEN1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[21]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[22]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Flap endonuclease GEN homolog 1 (GEN1).	[26]

References

• [1] Disruption of Gen1 Causes Congenital Anomalies of the Kidney and Urinary Tract in Mice.Int J Biol Sci. 2018 Jan 1;14(1):10-20. doi: 10.7150/ijbs.22768. eCollection 2018.
• [2] Progress in Confocal Laser Endomicroscopy for Neurosurgery and Technical Nuances for Brain Tumor Imaging With Fluorescein.Front Oncol. 2019 Jul 3;9:554. doi: 10.3389/fonc.2019.00554. eCollection 2019.
• [3] Earlier age of onset of BRCA mutation-related cancers in subsequent generations.Cancer. 2012 Jan 15;118(2):321-5. doi: 10.1002/cncr.26284. Epub 2011 Sep 12.
• [4] Maternal choline supplementation ameliorates Alzheimer's disease pathology by reducing brain homocysteine levels across multiple generations.Mol Psychiatry. 2020 Oct;25(10):2620-2629. doi: 10.1038/s41380-018-0322-z. Epub 2019 Jan 8.
• [5] Chemopreventive activity of GEN-27, a genistein derivative, in colitis-associated cancer is mediated by p65-CDX2--catenin axis.Oncotarget. 2016 Apr 5;7(14):17870-84. doi: 10.18632/oncotarget.7554.
• [6] GEN-1 immunotherapy for the treatment of ovarian cancer.Future Oncol. 2019 Feb;15(4):421-438. doi: 10.2217/fon-2018-0423. Epub 2018 Oct 16.
• [7] Therapeutic Vaccine for Genital Herpes Simplex Virus-2 Infection: Findings From a Randomized Trial.J Infect Dis. 2017 Mar 15;215(6):856-864. doi: 10.1093/infdis/jix004.
• [8] Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia reveals putative predisposing mutations in Fanconi anemia genes.BMC Cancer. 2015 Jul 23;15:539. doi: 10.1186/s12885-015-1549-6.
• [9] GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.Neurol Sci. 2019 Mar;40(3):561-570. doi: 10.1007/s10072-018-3664-z. Epub 2019 Jan 3.
• [10] GEN GEN: the genomic genetic analysis of androgen-metabolic genes and prostate cancer as a paradigm for the dissection of complex phenotypes.Front Biosci. 1999 Jul 15;4:D596-600. doi: 10.2741/reichardt.
• [11] A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study.Gynecol Oncol. 2017 Nov;147(2):283-290. doi: 10.1016/j.ygyno.2017.08.001. Epub 2017 Aug 10.
• [12] Systematic analysis of DNA crosslink repair pathways during development and aging in Caenorhabditis elegans.Nucleic Acids Res. 2017 Sep 19;45(16):9467-9480. doi: 10.1093/nar/gkx660.
• [13] Synergistic antibacterial effect of Bi(2)S(3) nanospheres combined with ineffective antibiotic gentamicin against methicillin-resistant Staphylococcus aureus.J Inorg Biochem. 2017 Mar;168:38-45. doi: 10.1016/j.jinorgbio.2016.12.005. Epub 2016 Dec 10.
• [14] Gen1 Modulates Metanephric Morphology Through Retinoic Acid Signaling.DNA Cell Biol. 2019 Mar;38(3):263-271. doi: 10.1089/dna.2018.4426. Epub 2019 Jan 11.
• [15] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [16] 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.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] 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.
• [19] Expression and localization of GEN1 in mouse mammary epithelial cells. J Biochem Mol Toxicol. 2014 Oct;28(10):450-5. doi: 10.1002/jbt.21584. Epub 2014 Jun 30.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [22] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.