Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8NVXTD)

• DOT Name: DNA replication complex GINS protein PSF3 (GINS3)
• Synonyms: GINS complex subunit 3
• Gene Name: GINS3
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Adenocarcinoma
  Advanced cancer
  Carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Endometrial carcinoma
  Neoplasm
• UniProt ID: PSF3_HUMAN
• PDB ID: 2E9X; 2EHO; 2Q9Q; 6XTX; 6XTY; 7PFO; 7PLO; 8B9D
• Pfam ID: PF05916
• Sequence:
  MSEAYFRVESGALGPEENFLSLDDILMSHEKLPVRTETAMPRLGAFFLERSAGAETDNAV
  PQGSKLELPLWLAKGLFDNKRRILSVELPKIYQEGWRTVFSADPNVVDLHKMGPHFYGFG
  SQLLHFDSPENADISQSLLQTFIGRFRRIMDSSQNAYNEDTSALVARLDEMERGLFQTGQ
  KGLNDFQCWEKGQASQITASNLVQNYKKRKFTDMED
• Function: Required for correct functioning of the GINS complex, a complex that plays an essential role in the initiation of DNA replication, and progression of DNA replication forks. GINS complex is a core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built.
• Reactome Pathway: Unwinding of DNA (R-HSA-176974)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[5]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]

3 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 DNA replication complex GINS protein PSF3 (GINS3).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of DNA replication complex GINS protein PSF3 (GINS3).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of DNA replication complex GINS protein PSF3 (GINS3).	[22]

19 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 DNA replication complex GINS protein PSF3 (GINS3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA replication complex GINS protein PSF3 (GINS3).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA replication complex GINS protein PSF3 (GINS3).	[16]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[17]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[18]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of DNA replication complex GINS protein PSF3 (GINS3).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of DNA replication complex GINS protein PSF3 (GINS3).	[25]

References

• [1] Induced expression of GINS complex is an essential step for reactivation of quiescent stem-like tumor cells within the peri-necrotic niche in human glioblastoma.J Cancer Res Clin Oncol. 2019 Feb;145(2):363-371. doi: 10.1007/s00432-018-2797-z. Epub 2018 Nov 21.
• [2] Psf3 as a possible biomarker of postoperative chemotherapy for patients with early pulmonary adenocarcinoma.Thorac Cancer. 2019 Dec;10(12):2300-2307. doi: 10.1111/1759-7714.13230. Epub 2019 Oct 22.
• [3] Clinicopathological significance of PSF3 expression in uterine endometrial carcinomas.Hum Pathol. 2018 Oct;80:104-112. doi: 10.1016/j.humpath.2018.06.010. Epub 2018 Jun 21.
• [4] PSF3 marks malignant colon cancer and has a role in cancer cell proliferation.Biochem Biophys Res Commun. 2010 Feb 5;392(2):150-4. doi: 10.1016/j.bbrc.2009.12.174. Epub 2010 Jan 6.
• [5] Partner of Sld five 3: a potential prognostic biomarker for colorectal cancer.Diagn Pathol. 2014 Nov 18;9:217. doi: 10.1186/s13000-014-0217-5.
• [6] 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.
• [7] 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.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] 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.
• [17] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [18] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [23] 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.
• [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] 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.