Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8JAQGL)

• DOT Name: Replication protein A 14 kDa subunit (RPA3)
• Synonyms: RP-A p14; Replication factor A protein 3; RF-A protein 3
• Gene Name: RPA3
• Related Disease:
  Colorectal carcinoma
  Gastric cancer
  Glioma
  Myelodysplastic syndrome
  Neoplasm
  Stomach cancer
  Bone osteosarcoma
  Hepatocellular carcinoma
  Osteosarcoma
  Head-neck squamous cell carcinoma
  Nasopharyngeal carcinoma
• UniProt ID: RFA3_HUMAN
• PDB ID: 1L1O; 1QUQ; 2PI2; 2PQA; 2Z6K; 3KDF
• Pfam ID: PF08661
• Sequence:
  MVDMMDLPRSRINAGMLAQFIDKPVCFVGRLEKIHPTGKMFILSDGEGKNGTIELMEPLD
  EEISGIVEVVGRVTAKATILCTSYVQFKEDSHPFDLGLYNEAVKIIHDFPQFYPLGIVQH
  D
• Function: As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage. In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response. It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin, in response to DNA damage. Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair. Also plays a role in base excision repair (BER), probably through interaction with UNG. Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance. RPA3 has its own single-stranded DNA-binding activity and may be responsible for polarity of the binding of the complex to DNA. As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA synthesis by polymerase delta in presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange.
• KEGG Pathway:
  D. replication (hsa03030)
  Nucleotide excision repair (hsa03420)
  Mismatch repair (hsa03430)
  Homologous recombi.tion (hsa03440)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)
  Translesion Synthesis by POLH (R-HSA-110320)
  Removal of the Flap Intermediate from the C-strand (R-HSA-174437)
  Activation of ATR in response to replication stress (R-HSA-176187)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  HSF1 activation (R-HSA-3371511)
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358565)
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358606)
  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)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  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)
  Fanconi Anemia Pathway (R-HSA-6783310)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  Activation of the pre-replicative complex (R-HSA-68962)
  Removal of the Flap Intermediate (R-HSA-69166)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Meiotic recombination (R-HSA-912446)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Translesion synthesis by REV1 (R-HSA-110312)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Genetic Variation	[3]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[6]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[5]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Altered Expression	[7]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Replication protein A 14 kDa subunit (RPA3) affects the response to substance of Doxorubicin.	[29]
Vinblastine	DM5TVS3	Approved	Replication protein A 14 kDa subunit (RPA3) affects the response to substance of Vinblastine.	[29]

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 Replication protein A 14 kDa subunit (RPA3).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Replication protein A 14 kDa subunit (RPA3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Replication protein A 14 kDa subunit (RPA3).	[27]

18 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 protein A 14 kDa subunit (RPA3).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Replication protein A 14 kDa subunit (RPA3).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Replication protein A 14 kDa subunit (RPA3).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Replication protein A 14 kDa subunit (RPA3).	[18]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Replication protein A 14 kDa subunit (RPA3).	[19]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[20]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[22]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Replication protein A 14 kDa subunit (RPA3).	[23]
Acocantherin	DM7JT24	Approved	Acocantherin affects the expression of Replication protein A 14 kDa subunit (RPA3).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Replication protein A 14 kDa subunit (RPA3).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Replication protein A 14 kDa subunit (RPA3).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Replication protein A 14 kDa subunit (RPA3).	[28]

References

• [1] Hsa_circ_101555 functions as a competing endogenous RNA of miR-597-5p to promote colorectal cancer progression.Oncogene. 2019 Aug;38(32):6017-6034. doi: 10.1038/s41388-019-0857-8. Epub 2019 Jul 12.
• [2] Elevated Expression of RPA3 Is Involved in Gastric Cancer Tumorigenesis and Associated with Poor Patient Survival.Dig Dis Sci. 2017 Sep;62(9):2369-2375. doi: 10.1007/s10620-017-4696-6. Epub 2017 Aug 1.
• [3] TP53 and RPA3 gene variations were associated with risk of glioma in a Chinese Han population.Cancer Biother Radiopharm. 2013 Apr;28(3):248-53. doi: 10.1089/cbr.2012.1291.
• [4] Differential expression of homologous recombination DNA repair genes in the early and advanced stages of myelodysplastic syndrome.Eur J Haematol. 2017 Oct;99(4):323-331. doi: 10.1111/ejh.12920. Epub 2017 Jul 24.
• [5] Identification of key biomarkers involved in osteosarcoma using altered modules.Genet Mol Res. 2016 Aug 26;15(3). doi: 10.4238/gmr.15038277.
• [6] MicroRNA-146a-5p enhances radiosensitivity in hepatocellular carcinoma through replication protein A3-induced activation of the DNA repair pathway.Am J Physiol Cell Physiol. 2019 Mar 1;316(3):C299-C311. doi: 10.1152/ajpcell.00189.2018. Epub 2018 Nov 21.
• [7] RPA3 is a potential marker of prognosis and radioresistance for nasopharyngeal carcinoma.J Cell Mol Med. 2017 Nov;21(11):2872-2883. doi: 10.1111/jcmm.13200. Epub 2017 May 30.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [14] 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.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [19] Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006 May;27(5):916-24. doi: 10.1093/carcin/bgi312. Epub 2005 Dec 16.
• [20] 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.
• [21] Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008 Feb;32(2):275-85. doi: 10.1016/j.leukres.2007.05.024. Epub 2007 Jul 19.
• [22] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [23] 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.
• [24] Proteomics analysis of the proliferative effect of low-dose ouabain on human endothelial cells. Biol Pharm Bull. 2007 Feb;30(2):247-53. doi: 10.1248/bpb.30.247.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Benzo(a)pyrene-induced cytotoxicity, cell proliferation, DNA damage, and altered gene expression profiles in HT-29 human colon cancer cells. Cell Biol Toxicol. 2021 Dec;37(6):891-913. doi: 10.1007/s10565-020-09579-5. Epub 2021 Jan 7.
• [27] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [29] 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.