Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLIYP8M)

• DOT Name: Origin recognition complex subunit 2 (ORC2)
• Gene Name: ORC2
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Clear cell renal carcinoma
• UniProt ID: ORC2_HUMAN
• PDB ID: 5C8H; 5UJ8; 5UJM; 7CTE; 7CTF; 7CTG; 7JPO; 7JPP; 7JPQ; 7JPR; 7JPS
• Pfam ID: PF04084
• Sequence:
  MSKPELKEDKMLEVHFVGDDDVLNHILDREGGAKLKKERAQLLVNPKKIIKKPEYDLEED
  DQEVLKDQNYVEIMGRDVQESLKNGSATGGGNKVYSFQNRKHSEKMAKLASELAKTPQKS
  VSFSLKNDPEITINVPQSSKGHSASDKVQPKNNDKSEFLSTAPRSLRKRLIVPRSHSDSE
  SEYSASNSEDDEGVAQEHEEDTNAVIFSQKIQAQNRVVSAPVGKETPSKRMKRDKTSDLV
  EEYFEAHSSSKVLTSDRTLQKLKRAKLDQQTLRNLLSKVSPSFSAELKQLNQQYEKLFHK
  WMLQLHLGFNIVLYGLGSKRDLLERFRTTMLQDSIHVVINGFFPGISVKSVLNSITEEVL
  DHMGTFRSILDQLDWIVNKFKEDSSLELFLLIHNLDSQMLRGEKSQQIIGQLSSLHNIYL
  IASIDHLNAPLMWDHAKQSLFNWLWYETTTYSPYTEETSYENSLLVKQSGSLPLSSLTHV
  LRSLTPNARGIFRLLIKYQLDNQDNPSYIGLSFQDFYQQCREAFLVNSDLTLRAQLTEFR
  DHKLIRTKKGTDGVEYLLIPVDNGTLTDFLEKEEEEA
• 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, H3K20me3 and H4K27me3. Stabilizes LRWD1, by protecting it from ubiquitin-mediated proteasomal degradation. Also stabilizes ORC3.
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Definitive	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Origin recognition complex subunit 2 (ORC2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Origin recognition complex subunit 2 (ORC2).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Origin recognition complex subunit 2 (ORC2).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Origin recognition complex subunit 2 (ORC2).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Origin recognition complex subunit 2 (ORC2).	[7]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Origin recognition complex subunit 2 (ORC2).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Origin recognition complex subunit 2 (ORC2).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Origin recognition complex subunit 2 (ORC2).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Origin recognition complex subunit 2 (ORC2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Origin recognition complex subunit 2 (ORC2).	[11]

References

• [1] Circ_ORC2 enhances the regulatory effect of miR-19a on its target gene PTEN to affect osteosarcoma cell growth.Biochem Biophys Res Commun. 2019 Jul 5;514(4):1172-1178. doi: 10.1016/j.bbrc.2019.04.188. Epub 2019 May 15.
• [2] Global analysis of metastasis-associated gene expression in primary cultures from clinical specimens of clear-cell renal-cell carcinoma.Int J Cancer. 2008 Sep 1;123(5):1080-8. doi: 10.1002/ijc.23637.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] 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.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [7] Progestins regulate genes that can elicit both proliferative and antiproliferative effects in breast cancer cells. Oncol Rep. 2008 Jun;19(6):1627-34.
• [8] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] 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.