Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCVOO3S)

• DOT Name: DNA replication complex GINS protein SLD5 (GINS4)
• Synonyms: GINS complex subunit 4
• Gene Name: GINS4
• Related Disease:
  Gastric cancer
  Stomach cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Rothmund-Thomson syndrome
  Influenza
  Neoplasm
• UniProt ID: SLD5_HUMAN
• PDB ID: 2E9X; 2EHO; 2Q9Q; 6XTX; 6XTY; 7PFO; 7PLO; 8B9D
• Pfam ID: PF05916 ; PF16922
• Sequence:
  MTEEVDFLGQDSDGGSEEVVLTPAELIERLEQAWMNEKFAPELLESKPEIVECVMEQLEH
  MEENLRRAKREDLKVSIHQMEMERIRYVLSSYLRCRLMKIEKFFPHVLEKEKTRPEGEPS
  SLSPEELAFAREFMANTESYLKNVALKHMPPNLQKVDLFRAVPKPDLDSYVFLRVRERQE
  NILVEPDTDEQRDYVIDLEKGSQHLIRYKTIAPLVASGAVQLI
• 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

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Biomarker	[1]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Rothmund-Thomson syndrome	DISGVBCV	Strong	Biomarker	[3]
Influenza	DIS3PNU3	moderate	Altered Expression	[4]
Neoplasm	DISZKGEW	Limited	Altered Expression	[1]

14 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 SLD5 (GINS4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[11]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[13]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[18]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of DNA replication complex GINS protein SLD5 (GINS4).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA replication complex GINS protein SLD5 (GINS4).	[15]

References

• [1] The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42.Theranostics. 2019 Oct 21;9(26):8294-8311. doi: 10.7150/thno.36256. eCollection 2019.
• [2] LSH interacts with and stabilizes GINS4 transcript that promotes tumourigenesis in non-small cell lung cancer.J Exp Clin Cancer Res. 2019 Jun 28;38(1):280. doi: 10.1186/s13046-019-1276-y.
• [3] Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome.Cell. 2005 Jun 17;121(6):887-98. doi: 10.1016/j.cell.2005.05.015.
• [4] Influenza virus matrix protein M1 interacts with SLD5 to block host cell cycle.Cell Microbiol. 2019 Aug;21(8):e13038. doi: 10.1111/cmi.13038. Epub 2019 May 16.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] 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.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] 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.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.