Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEQEFQ2)

• DOT Name: DNA polymerase delta subunit 3 (POLD3)
• Synonyms: DNA polymerase delta subunit C; DNA polymerase delta subunit p66; DNA polymerase delta subunit p68
• Gene Name: POLD3
• Related Disease:
  Adrenal cortex neoplasm
  Advanced cancer
  Autoimmune disease
  Cervical cancer
  Cervical carcinoma
  Chromosomal disorder
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal neoplasm
  Craniosynostosis
  Fibrosarcoma
  Head-neck squamous cell carcinoma
  Influenza
  Lyme disease
  Medulloblastoma
  Myopathy
  Obesity
  Polycystic ovarian syndrome
  Prostate cancer
  Prostate carcinoma
  Colorectal carcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Castration-resistant prostate carcinoma
  Colon carcinoma
  Invasive ductal breast carcinoma
• UniProt ID: DPOD3_HUMAN
• PDB ID: 1U76; 2N1G; 3E0J; 6S1M; 6S1N; 6S1O; 6TNY; 6TNZ
• Pfam ID: PF09507
• Sequence:
  MADQLYLENIDEFVTDQNKIVTYKWLSYTLGVHVNQAKQMLYDYVERKRKENSGAQLHVT
  YLVSGSLIQNGHSCHKVAVVREDKLEAVKSKLAVTASIHVYSIQKAMLKDSGPLFNTDYD
  ILKSNLQNCSKFSAIQCAAAVPRAPAESSSSSKKFEQSHLHMSSETQANNELTTNGHGPP
  ASKQVSQQPKGIMGMFASKAAAKTQETNKETKTEAKEVTNASAAGNKAPGKGNMMSNFFG
  KAAMNKFKVNLDSEQAVKEEKIVEQPTVSVTEPKLATPAGLKKSSKKAEPVKVLQKEKKR
  GKRVALSDDETKETENMRKKRRRIKLPESDSSEDEVFPDSPGAYEAESPSPPPPPSPPLE
  PVPKTEPEPPSVKSSSGENKRKRKRVLKSKTYLDGEGCIVTEKVYESESCTDSEEELNMK
  TSSVHRPPAMTVKKEPREERKGPKKGTAALGKANRQVSITGFFQRK
• Function: Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex. As a component of the trimeric and tetrameric DNA polymerase delta complexes (Pol-delta3 and Pol-delta4, respectively), plays a role in high fidelity genome replication, including in lagging strand synthesis, and repair. Required for optimal Pol-delta activity. Stabilizes the Pol-delta complex and plays a major role in Pol-delta stimulation by PCNA. Pol-delta3 and Pol-delta4 are characterized by the absence or the presence of POLD4. They exhibit differences in catalytic activity. Most notably, Pol-delta3 shows higher proofreading activity than Pol-delta4. Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may also be better suited to fulfill this task, exhibiting near-absence of strand displacement activity compared to Pol-delta4 and stalling on encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling process may avoid the formation of a gap, while maintaining a nick that can be readily ligated. Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation. In this context, POLD3, along with PCNA and RFC1-replication factor C complex, is required to recruit POLD1, the catalytic subunit of the polymerase delta complex, to DNA damage sites. Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites performed by Pol-delta4, independently of DNA polymerase zeta (REV3L) or eta (POLH). Facilitates abasic site bypass by DNA polymerase delta by promoting extension from the nucleotide inserted opposite the lesion. Also involved in TLS, as a component of the tetrametric DNA polymerase zeta complex. Along with POLD2, dramatically increases the efficiency and processivity of DNA synthesis of the DNA polymerase zeta complex compared to the minimal zeta complex, consisting of only REV3L and REV7.
• KEGG Pathway:
  D. replication (hsa03030)
  Base excision repair (hsa03410)
  Nucleotide excision repair (hsa03420)
  Mismatch repair (hsa03430)
  Homologous recombi.tion (hsa03440)
• Reactome Pathway:
  Polymerase switching on the C-strand of the telomere (R-HSA-174411)
  Processive synthesis on the C-strand of the telomere (R-HSA-174414)
  Telomere C-strand (Lagging Strand) Synthesis (R-HSA-174417)
  Removal of the Flap Intermediate from the C-strand (R-HSA-174437)
  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)
  Termination of translesion DNA synthesis (R-HSA-5656169)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  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)
  Polymerase switching (R-HSA-69091)
  Removal of the Flap Intermediate (R-HSA-69166)
  Processive synthesis on the lagging strand (R-HSA-69183)
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenal cortex neoplasm	DISO17X1	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Genetic Variation	[6]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[6]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[7]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[6]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[6]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[6]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[6]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[6]
Craniosynostosis	DIS6J405	Strong	Biomarker	[8]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[9]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[10]
Influenza	DIS3PNU3	Strong	Biomarker	[11]
Lyme disease	DISO70G5	Strong	Biomarker	[12]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[13]
Myopathy	DISOWG27	Strong	Biomarker	[14]
Obesity	DIS47Y1K	Strong	Genetic Variation	[15]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Colorectal carcinoma	DIS5PYL0	moderate	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Limited	Biomarker	[2]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[2]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[17]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[16]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[18]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA polymerase delta subunit 3 (POLD3).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA polymerase delta subunit 3 (POLD3).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA polymerase delta subunit 3 (POLD3).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA polymerase delta subunit 3 (POLD3).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA polymerase delta subunit 3 (POLD3).	[27]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[28]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[29]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[30]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA polymerase delta subunit 3 (POLD3).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of DNA polymerase delta subunit 3 (POLD3).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[36]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA polymerase delta subunit 3 (POLD3).	[37]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of DNA polymerase delta subunit 3 (POLD3).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA polymerase delta subunit 3 (POLD3).	[34]

References

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• [11] Purification and partial characterization of a cellular inhibitor of the interferon-induced protein kinase of Mr 68,000 from influenza virus-infected cells.Proc Natl Acad Sci U S A. 1990 Aug;87(16):6208-12. doi: 10.1073/pnas.87.16.6208.
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• [17] DEAD-box protein p68 is regulated by -catenin/transcription factor 4 to maintain a positive feedback loop in control of breast cancer progression.Breast Cancer Res. 2014 Dec 12;16(6):496. doi: 10.1186/s13058-014-0496-5.
• [18] The DEAD box protein p68: a novel coactivator of Stat3 in mediating oncogenesis.Oncogene. 2017 Jun 1;36(22):3080-3093. doi: 10.1038/onc.2016.449. Epub 2016 Dec 12.
• [19] Expression of the double-stranded RNA-dependent protein kinase (p68) in human breast tissues.Tumour Biol. 1996;17(1):5-12. doi: 10.1159/000217961.
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• [25] 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.
• [26] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
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• [32] 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.
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• [35] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [36] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [37] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [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.