Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ACTST)

• DOT Name: Origin recognition complex subunit 4 (ORC4)
• Gene Name: ORC4
• Related Disease:
  Meier-Gorlin syndrome 2
  Breast cancer
  Common variable immunodeficiency
  Gout
  Lymphoma, non-Hodgkin, familial
  Lymphoproliferative syndrome
  Myeloproliferative neoplasm
  Non-hodgkin lymphoma
  Plasma cell myeloma
  Seckel syndrome
  Meier-Gorlin syndrome
  Isolated congenital microcephaly
  Pulmonary emphysema
• UniProt ID: ORC4_HUMAN
• PDB ID: 5UJ7; 5UJM; 7CTE; 7CTF; 7CTG; 7JPO; 7JPP; 7JPQ; 7JPR; 7JPS
• Pfam ID: PF13191 ; PF14629
• Sequence:
  MSSRKSKSNSLIHTECLSQVQRILRERFCRQSPHSNLFGVQVQYKHLSELLKRTALHGES
  NSVLIIGPRGSGKTMLINHALKELMEIEEVSENVLQVHLNGLLQINDKIALKEITRQLNL
  ENVVGDKVFGSFAENLSFLLEALKKGDRTSSCPVIFILDEFDLFAHHKNQTLLYNLFDIS
  QSAQTPIAVIGLTCRLDILELLEKRVKSRFSHRQIHLMNSFGFPQYVKIFKEQLSLPAEF
  PDKVFAEKWNENVQYLSEDRSVQEVLQKHFNISKNLRSLHMLLMLALNRVTASHPFMTAV
  DLMEASQLCSMDSKANIVHGLSVLEICLIIAMKHLNDIYEEEPFNFQMVYNEFQKFVQRK
  AHSVYNFEKPVVMKAFEHLQQLELIKPMERTSGNSQREYQLMKLLLDNTQIMNALQKYPN
  CPTDVRQWATSSLSWL
• Function: Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  Activation of ATR in response to replication stress (R-HSA-176187)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  CDC6 association with the ORC (R-HSA-68689)
  Assembly of the pre-replicative complex (R-HSA-68867)
  Orc1 removal from chromatin (R-HSA-68949)
  Activation of the pre-replicative complex (R-HSA-68962)
  E2F-enabled inhibition of pre-replication complex formation (R-HSA-113507)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Meier-Gorlin syndrome 2	DISTWCTG	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Common variable immunodeficiency	DISHE7JQ	Strong	Genetic Variation	[3]
Gout	DISHC0U7	Strong	Genetic Variation	[4]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Genetic Variation	[5]
Lymphoproliferative syndrome	DISMVL8O	Strong	Genetic Variation	[5]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Biomarker	[6]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[5]
Seckel syndrome	DISEVUBA	Strong	Biomarker	[6]
Meier-Gorlin syndrome	DISCFIU3	Supportive	Autosomal dominant	[7]
Isolated congenital microcephaly	DISUXHZ6	Limited	Genetic Variation	[8]
Pulmonary emphysema	DIS5M7HZ	Limited	Biomarker	[9]

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 Origin recognition complex subunit 4 (ORC4).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Origin recognition complex subunit 4 (ORC4).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Origin recognition complex subunit 4 (ORC4).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Origin recognition complex subunit 4 (ORC4).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Origin recognition complex subunit 4 (ORC4).	[15]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Origin recognition complex subunit 4 (ORC4).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Origin recognition complex subunit 4 (ORC4).	[17]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Origin recognition complex subunit 4 (ORC4).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Origin recognition complex subunit 4 (ORC4).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Origin recognition complex subunit 4 (ORC4).	[19]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Origin recognition complex subunit 4 (ORC4).	[20]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Origin recognition complex subunit 4 (ORC4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Origin recognition complex subunit 4 (ORC4).	[12]

References

• [1] Meier-Gorlin syndrome: report of eight additional cases and review. Am J Med Genet. 2001 Aug 1;102(2):115-24. doi: 10.1002/ajmg.1452.
• [2] Inconsistent Results With Different Secondary Reflex Assays for Resolving HER2 Status.Am J Clin Pathol. 2016 Nov 1;146(5):618-626. doi: 10.1093/ajcp/aqw177.
• [3] Genome-wide association identifies diverse causes of common variable immunodeficiency.J Allergy Clin Immunol. 2011 Jun;127(6):1360-7.e6. doi: 10.1016/j.jaci.2011.02.039. Epub 2011 Apr 17.
• [4] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [5] Novel ORC4L gene mutation in B-cell lymphoproliferative disorders.Am J Med Sci. 2009 Dec;338(6):527-9. doi: 10.1097/MAJ.0b013e3181b7f17c.
• [6] Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet. 2011 Feb 27;43(4):356-9. doi: 10.1038/ng.775.
• [7] Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of Meier-Gorlin syndrome. PLoS Genet. 2013;9(3):e1003360. doi: 10.1371/journal.pgen.1003360. Epub 2013 Mar 14.
• [8] Meier-Gorlin syndrome.Orphanet J Rare Dis. 2015 Sep 17;10:114. doi: 10.1186/s13023-015-0322-x.
• [9] Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis.Eur J Hum Genet. 2012 Jun;20(6):598-606. doi: 10.1038/ejhg.2011.269. Epub 2012 Feb 15.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [14] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [15] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [16] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [17] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [18] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] 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.
• [21] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.