Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYQWB6B)

• DOT Name: Origin recognition complex subunit 3 (ORC3)
• Synonyms: Origin recognition complex subunit Latheo
• Gene Name: ORC3
• Related Disease: Meier-Gorlin syndrome
• UniProt ID: ORC3_HUMAN
• PDB ID: 5UJ8; 5UJM; 7CTE; 7CTF; 7CTG; 7JPO; 7JPP; 7JPQ; 7JPR; 7JPS
• Pfam ID: PF19675 ; PF07034 ; PF18137
• Sequence:
  MATSSMSKGCFVFKPNSKKRKISLPIEDYFNKGKNEPEDSKLRFETYQLIWQQMKSENER
  LQEELNKNLFDNLIEFLQKSHSGFQKNSRDLGGQIKLREIPTAALVLGVNVTDHDLTFGS
  LTEALQNNVTPYVVSLQAKDCPDMKHFLQKLISQLMDCCVDIKSKEEESVHVTQRKTHYS
  MDSLSSWYMTVTQKTDPKMLSKKRTTSSQWQSPPVVVILKDMESFATKVLQDFIIISSQH
  LHEFPLILIFGIATSPIIIHRLLPHAVSSLLCIELFQSLSCKEHLTTVLDKLLLTTQFPF
  KINEKVLQVLTNIFLYHDFSVQNFIKGLQLSLLEHFYSQPLSVLCCNLPEAKRRINFLSN
  NQCENIRRLPSFRRYVEKQASEKQVALLTNERYLKEETQLLLENLHVYHMNYFLVLRCLH
  KFTSSLPKYPLGRQIRELYCTCLEKNIWDSEEYASVLQLLRMLAKDELMTILEKCFKVFK
  SYCENHLGSTAKRIEEFLAQFQSLDETKEEEDASGSQPKGLQKTDLYHLQKSLLEMKELR
  RSKKQTKFEVLRENVVNFIDCLVREYLLPPETQPLHEVVYFSAAHALREHLNAAPRIALH
  TALNNPYYYLKNEALKSEEGCIPNIAPDICIAYKLHLECSRLINLVDWSEAFATVVTAAE
  KMDANSATSEEMNEIIHARFIRAVSELELLGFIKPTKQKTDHVARLTWGGC
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Meier-Gorlin syndrome	DISCFIU3	Strong	Genetic Variation	[1]

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 Origin recognition complex subunit 3 (ORC3).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Origin recognition complex subunit 3 (ORC3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Origin recognition complex subunit 3 (ORC3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Origin recognition complex subunit 3 (ORC3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Origin recognition complex subunit 3 (ORC3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Origin recognition complex subunit 3 (ORC3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Origin recognition complex subunit 3 (ORC3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Origin recognition complex subunit 3 (ORC3).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Origin recognition complex subunit 3 (ORC3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Origin recognition complex subunit 3 (ORC3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Origin recognition complex subunit 3 (ORC3).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Origin recognition complex subunit 3 (ORC3).	[13]

References

• [1] A Meier-Gorlin syndrome mutation in a conserved C-terminal helix of Orc6 impedes origin recognition complex formation.Elife. 2013 Oct 8;2:e00882. doi: 10.7554/eLife.00882.
• [2] 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.
• [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] 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.
• [5] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
• [9] 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.
• [10] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.