Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1MS7AO)

• DOT Name: Replication factor C subunit 3 (RFC3)
• Synonyms: Activator 1 38 kDa subunit; A1 38 kDa subunit; Activator 1 subunit 3; Replication factor C 38 kDa subunit; RF-C 38 kDa subunit; RFC38
• Gene Name: RFC3
• Related Disease:
  Epithelial ovarian cancer
  Ovarian cancer
  Acute myelogenous leukaemia
  Advanced cancer
  Barrett esophagus
  Differentiated thyroid carcinoma
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Gastric cancer
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Stomach cancer
  Triple negative breast cancer
  Neoplasm
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
• UniProt ID: RFC3_HUMAN
• PDB ID: 6VVO; 7Z6H
• Pfam ID: PF13177
• Sequence:
  MSLWVDKYRPCSLGRLDYHKEQAAQLRNLVQCGDFPHLLVYGPSGAGKKTRIMCILRELY
  GVGVEKLRIEHQTITTPSKKKIEISTIASNYHLEVNPSDAGNSDRVVIQEMLKTVAQSQQ
  LETNSQRDFKVVLLTEVDKLTKDAQHALRRTMEKYMSTCRLILCCNSTSKVIPPIRSRCL
  AVRVPAPSIEDICHVLSTVCKKEGLNLPSQLAHRLAEKSCRNLRKALLMCEACRVQQYPF
  TADQEIPETDWEVYLRETANAIVSQQTPQRLLEVRGRLYELLTHCIPPEIIMKGLLSELL
  HNCDGQLKGEVAQMAAYYEHRLQLGSKAIYHLEAFVAKFMALYKKFMEDGLEGMMF
• 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

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[1]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[3]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Genetic Variation	[4]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[3]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[5]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	moderate	Altered Expression	[8]
Breast cancer	DIS7DPX1	Disputed	Biomarker	[9]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[10]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Replication factor C subunit 3 (RFC3) affects the response to substance of Fluorouracil.	[40]
Mitomycin	DMH0ZJE	Approved	Replication factor C subunit 3 (RFC3) affects the response to substance of Mitomycin.	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Replication factor C subunit 3 (RFC3).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Replication factor C subunit 3 (RFC3).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Replication factor C subunit 3 (RFC3).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Replication factor C subunit 3 (RFC3).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Replication factor C subunit 3 (RFC3).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Replication factor C subunit 3 (RFC3).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Replication factor C subunit 3 (RFC3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Replication factor C subunit 3 (RFC3).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Replication factor C subunit 3 (RFC3).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Replication factor C subunit 3 (RFC3).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Replication factor C subunit 3 (RFC3).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Replication factor C subunit 3 (RFC3).	[20]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Replication factor C subunit 3 (RFC3).	[22]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Replication factor C subunit 3 (RFC3).	[23]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Replication factor C subunit 3 (RFC3).	[24]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Replication factor C subunit 3 (RFC3).	[25]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Replication factor C subunit 3 (RFC3).	[26]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Replication factor C subunit 3 (RFC3).	[27]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Replication factor C subunit 3 (RFC3).	[28]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Replication factor C subunit 3 (RFC3).	[29]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Replication factor C subunit 3 (RFC3).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Replication factor C subunit 3 (RFC3).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Replication factor C subunit 3 (RFC3).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Replication factor C subunit 3 (RFC3).	[34]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Replication factor C subunit 3 (RFC3).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Replication factor C subunit 3 (RFC3).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Replication factor C subunit 3 (RFC3).	[37]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Replication factor C subunit 3 (RFC3).	[17]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Replication factor C subunit 3 (RFC3).	[38]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Replication factor C subunit 3 (RFC3).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Replication factor C subunit 3 (RFC3).	[33]

References

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• [2] Replication factor C3 is a CREB target gene that regulates cell cycle progression through the modulation of chromatin loading of PCNA.Leukemia. 2015 Jun;29(6):1379-89. doi: 10.1038/leu.2014.350. Epub 2014 Dec 26.
• [3] Integrative genomics identified RFC3 as an amplified candidate oncogene in esophageal adenocarcinoma.Clin Cancer Res. 2012 Apr 1;18(7):1936-46. doi: 10.1158/1078-0432.CCR-11-1431. Epub 2012 Feb 10.
• [4] Polymorphisms within base and nucleotide excision repair pathways and risk of differentiated thyroid carcinoma.DNA Repair (Amst). 2016 May;41:27-31. doi: 10.1016/j.dnarep.2016.03.011. Epub 2016 Mar 31.
• [5] Detection of coding microsatellite frameshift mutations in DNA mismatch repair-deficient mouse intestinal tumors.Mol Carcinog. 2015 Nov;54(11):1376-86. doi: 10.1002/mc.22213. Epub 2014 Sep 11.
• [6] shRNA-mediated silencing of the RFC3 gene suppresses hepatocellular carcinoma cell proliferation.Int J Mol Med. 2015 Nov;36(5):1393-9. doi: 10.3892/ijmm.2015.2350. Epub 2015 Sep 21.
• [7] RFC3 induces epithelialmesenchymal transition in lung adenocarcinoma cells through the Wnt/catenin pathway and possesses prognostic value in lung adenocarcinoma.Int J Mol Med. 2019 Dec;44(6):2276-2288. doi: 10.3892/ijmm.2019.4386. Epub 2019 Oct 29.
• [8] Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT.Transl Oncol. 2017 Feb;10(1):1-9. doi: 10.1016/j.tranon.2016.10.004. Epub 2016 Nov 23.
• [9] Downregulation of hsa_circ_0011946 suppresses the migration and invasion of the breast cancer cell line MCF-7 by targeting RFC3.Cancer Manag Res. 2018 Mar 19;10:535-544. doi: 10.2147/CMAR.S155923. eCollection 2018.
• [10] Mutational and expressional analysis of RFC3, a clamp loader in DNA replication, in gastric and colorectal cancers.Hum Pathol. 2010 Oct;41(10):1431-7. doi: 10.1016/j.humpath.2010.03.006. Epub 2010 Jun 22.
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• [32] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [33] 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.
• [34] 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.
• [35] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [36] 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.
• [37] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [38] 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.
• [39] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [40] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.
• [41] 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.