Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAD79RT)

• DOT Name: Replication factor C subunit 5 (RFC5)
• Synonyms: Activator 1 36 kDa subunit; A1 36 kDa subunit; Activator 1 subunit 5; Replication factor C 36 kDa subunit; RF-C 36 kDa subunit; RFC36
• Gene Name: RFC5
• Related Disease:
  Lung cancer
  Lung carcinoma
• UniProt ID: RFC5_HUMAN
• PDB ID: 6VVO; 7Z6H
• Pfam ID: PF00004 ; PF08542
• Sequence:
  METSALKQQEQPAATKIRNLPWVEKYRPQTLNDLISHQDILSTIQKFINEDRLPHLLLYG
  PPGTGKTSTILACAKQLYKDKEFGSMVLELNASDDRGIDIIRGPILSFASTRTIFKKGFK
  LVILDEADAMTQDAQNALRRVIEKFTENTRFCLICNYLSKIIPALQSRCTRFRFGPLTPE
  LMVPRLEHVVEEEKVDISEDGMKALVTLSSGDMRRALNILQSTNMAFGKVTEETVYTCTG
  HPLKSDIANILDWMLNQDFTTAYRNITELKTLKGLALHDILTEIHLFVHRVDFPSSVRIH
  LLTKMADIEYRLSVGTNEKIQLSSLIAAFQVTRDLIVAEA
• Function: The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1.
• KEGG Pathway:
  D. replication (hsa03030)
  Base excision repair (hsa03410)
  Nucleotide excision repair (hsa03420)
  Mismatch repair (hsa03430)
• Reactome Pathway:
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)
  Translesion Synthesis by POLH (R-HSA-110320)
  Polymerase switching on the C-strand of the telomere (R-HSA-174411)
  Activation of ATR in response to replication stress (R-HSA-176187)
  PCNA-Dependent Long Patch Base Excision Repair (R-HSA-5651801)
  Translesion synthesis by POLK (R-HSA-5655862)
  Translesion synthesis by POLI (R-HSA-5656121)
  Termination of translesion DNA synthesis (R-HSA-5656169)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Gap-filling DNA repair synthesis and ligation in GG-NER (R-HSA-5696397)
  Dual Incision in GG-NER (R-HSA-5696400)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  Polymerase switching (R-HSA-69091)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Translesion synthesis by REV1 (R-HSA-110312)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Replication factor C subunit 5 (RFC5) affects the response to substance of Vinblastine.	[26]

25 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 Replication factor C subunit 5 (RFC5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Replication factor C subunit 5 (RFC5).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Replication factor C subunit 5 (RFC5).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Replication factor C subunit 5 (RFC5).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Replication factor C subunit 5 (RFC5).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Replication factor C subunit 5 (RFC5).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Replication factor C subunit 5 (RFC5).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Replication factor C subunit 5 (RFC5).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Replication factor C subunit 5 (RFC5).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Replication factor C subunit 5 (RFC5).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Replication factor C subunit 5 (RFC5).	[12]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Replication factor C subunit 5 (RFC5).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Replication factor C subunit 5 (RFC5).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Replication factor C subunit 5 (RFC5).	[15]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Replication factor C subunit 5 (RFC5).	[16]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Replication factor C subunit 5 (RFC5).	[17]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Replication factor C subunit 5 (RFC5).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Replication factor C subunit 5 (RFC5).	[3]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Replication factor C subunit 5 (RFC5).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Replication factor C subunit 5 (RFC5).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Replication factor C subunit 5 (RFC5).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Replication factor C subunit 5 (RFC5).	[22]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Replication factor C subunit 5 (RFC5).	[23]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Replication factor C subunit 5 (RFC5).	[24]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Replication factor C subunit 5 (RFC5).	[25]

References

• [1] Identification of RFC5 as a novel potential prognostic biomarker in lung cancer through bioinformatics analysis.Oncol Lett. 2018 Oct;16(4):4201-4210. doi: 10.3892/ol.2018.9221. Epub 2018 Jul 26.
• [2] 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.
• [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] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [10] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [11] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] 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.
• [16] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [17] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [18] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [19] Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis. Environ Mol Mutagen. 2009 Jan;50(1):46-59.
• [20] Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands. Toxicol Lett. 2011 Oct 10;206(2):178-88.
• [21] 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.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [24] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [25] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.