Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ54WAF)

• DOT Name: Replication protein A 32 kDa subunit (RPA2)
• Synonyms: RP-A p32; Replication factor A protein 2; RF-A protein 2; Replication protein A 34 kDa subunit; RP-A p34
• Gene Name: RPA2
• Related Disease:
  Advanced cancer
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Ductal carcinoma
  Fanconi anemia complementation group D2
  Multiple endocrine neoplasia
  Multiple endocrine neoplasia type 1
  Neoplasm
• UniProt ID: RFA2_HUMAN
• PDB ID: 1DPU; 1L1O; 1QUQ; 1Z1D; 2PI2; 2PQA; 2Z6K; 3KDF; 4MQV; 4OU0
• Pfam ID: PF08784
• Sequence:
  MWNSGFESYGSSSYGGAGGYTQSPGGFGSPAPSQAEKKSRARAQHIVPCTISQLLSATLV
  DEVFRIGNVEISQVTIVGIIRHAEKAPTNIVYKIDDMTAAPMDVRQWVDTDDTSSENTVV
  PPETYVKVAGHLRSFQNKKSLVAFKIMPLEDMNEFTTHILEVINAHMVLSKANSQPSAGR
  APISNPGMSEAGNFGGNSFMPANGLTVAQNQVLNLIKACPRPEGLNFQDLKNQLKHMSVS
  SIKQAVDFLSNEGHIYSTVDDDHFKSTDAE
• 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.
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[2]
Fanconi anemia complementation group D2	DISC76W3	Strong	Biomarker	[5]
Multiple endocrine neoplasia	DISZGBKW	Strong	Biomarker	[6]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Replication protein A 32 kDa subunit (RPA2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Replication protein A 32 kDa subunit (RPA2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Replication protein A 32 kDa subunit (RPA2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Replication protein A 32 kDa subunit (RPA2).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[15]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Replication protein A 32 kDa subunit (RPA2).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Replication protein A 32 kDa subunit (RPA2).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[22]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Replication protein A 32 kDa subunit (RPA2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Liothyronine	DM6IR3P	Approved	Liothyronine increases the phosphorylation of Replication protein A 32 kDa subunit (RPA2).	[17]
Etretinate	DM2CZFA	Approved	Etretinate increases the phosphorylation of Replication protein A 32 kDa subunit (RPA2).	[18]
Artesunate	DMR27C8	Approved	Artesunate increases the phosphorylation of Replication protein A 32 kDa subunit (RPA2).	[19]
AC220	DM8Y4JS	Approved	AC220 increases the phosphorylation of Replication protein A 32 kDa subunit (RPA2).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Replication protein A 32 kDa subunit (RPA2).	[23]
RGFP966	DME9T0A	Investigative	RGFP966 increases the phosphorylation of Replication protein A 32 kDa subunit (RPA2).	[20]

References

• [1] The molecular differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinoma: A bioinformatics study.Am J Otolaryngol. 2019 Jul-Aug;40(4):547-554. doi: 10.1016/j.amjoto.2019.04.015. Epub 2019 Apr 23.
• [2] Autoimmunity to the M(r) 32,000 subunit of replication protein A in breast cancer.Clin Cancer Res. 2002 Mar;8(3):752-8.
• [3] Upregulation of RPA2 promotes NF-B activation in breast cancer by relieving the antagonistic function of menin on NF-B-regulated transcription.Carcinogenesis. 2017 Feb 1;38(2):196-206. doi: 10.1093/carcin/bgw123.
• [4] Proteomic analysis of BRCA1-depleted cell line reveals a putative role for replication protein A2 up-regulation in BRCA1 breast tumor development.Proteomics Clin Appl. 2010 May;4(5):489-98. doi: 10.1002/prca.200900107. Epub 2010 Jan 4.
• [5] The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability.Hum Mol Genet. 2005 Mar 1;14(5):693-701. doi: 10.1093/hmg/ddi065. Epub 2005 Jan 20.
• [6] The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene.Mol Cell Biol. 2003 Jan;23(2):493-509. doi: 10.1128/MCB.23.2.493-509.2003.
• [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] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [14] 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.
• [15] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] Identification of small molecule proliferating cell nuclear antigen (PCNA) inhibitor that disrupts interactions with PIP-box proteins and inhibits DNA replication. J Biol Chem. 2012 Apr 20;287(17):14289-300. doi: 10.1074/jbc.M112.353201. Epub 2012 Mar 1.
• [18] Synthesis and structure-activity relationships of new antiproliferative and proapoptotic retinoid-related biphenyl-4-yl-acrylic acids. Bioorg Med Chem. 2007 Jul 15;15(14):4863-75. doi: 10.1016/j.bmc.2007.04.057. Epub 2007 May 3.
• [19] Induction of APOBEC3C Facilitates the Genotoxic Stress-Mediated Cytotoxicity of Artesunate. Chem Res Toxicol. 2019 Dec 16;32(12):2526-2537. doi: 10.1021/acs.chemrestox.9b00358. Epub 2019 Nov 11.
• [20] Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3. Arch Toxicol. 2022 Jan;96(1):177-193. doi: 10.1007/s00204-021-03174-1. Epub 2021 Oct 19.
• [21] 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.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] 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.