Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBNASP6)

• DOT Name: DNA polymerase delta subunit 2 (POLD2)
• Synonyms: DNA polymerase delta subunit p50
• Gene Name: POLD2
• Related Disease:
  Bladder transitional cell carcinoma
  Carcinoma
  Esophageal squamous cell carcinoma
  Ovarian cancer
  Nervous system disease
  Non-severe combined immunodeficiency due to polymerase delta deficiency
• UniProt ID: DPOD2_HUMAN
• PDB ID: 3E0J; 6S1M; 6S1N; 6S1O; 6TNY; 6TNZ
• Pfam ID: PF18018 ; PF04042
• Sequence:
  MFSEQAAQRAHTLLSPPSANNATFARVPVATYTNSSQPFRLGERSFSRQYAHIYATRLIQ
  MRPFLENRAQQHWGSGVGVKKLCELQPEEKCCVVGTLFKAMPLQPSILREVSEEHNLLPQ
  PPRSKYIHPDDELVLEDELQRIKLKGTIDVSKLVTGTVLAVFGSVRDDGKFLVEDYCFAD
  LAPQKPAPPLDTDRFVLLVSGLGLGGGGGESLLGTQLLVDVVTGQLGDEGEQCSAAHVSR
  VILAGNLLSHSTQSRDSINKAKYLTKKTQAASVEAVKMLDEILLQLSASVPVDVMPGEFD
  PTNYTLPQQPLHPCMFPLATAYSTLQLVTNPYQATIDGVRFLGTSGQNVSDIFRYSSMED
  HLEILEWTLRVRHISPTAPDTLGCYPFYKTDPFIFPECPHVYFCGNTPSFGSKIIRGPED
  QTVLLVTVPDFSATQTACLVNLRSLACQPISFSGFGAEDDDLGGLGLGP
• 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. 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. 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 DNA polymerase zeta complex. Along with POLD3, 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[3]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[4]
Non-severe combined immunodeficiency due to polymerase delta deficiency	DISQOWUX	Limited	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA polymerase delta subunit 2 (POLD2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA polymerase delta subunit 2 (POLD2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA polymerase delta subunit 2 (POLD2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA polymerase delta subunit 2 (POLD2).	[9]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of DNA polymerase delta subunit 2 (POLD2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA polymerase delta subunit 2 (POLD2).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA polymerase delta subunit 2 (POLD2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA polymerase delta subunit 2 (POLD2).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DNA polymerase delta subunit 2 (POLD2).	[12]

References

• [1] CAD/POLD2 gene expression is associated with poor overall survival and chemoresistance in bladder urothelial carcinoma.Oncotarget. 2018 Jul 3;9(51):29743-29752. doi: 10.18632/oncotarget.25701. eCollection 2018 Jul 3.
• [2] POLD2 and KSP37 (FGFBP2) correlate strongly with histology, stage and outcome in ovarian carcinomas.PLoS One. 2010 Nov 4;5(11):e13837. doi: 10.1371/journal.pone.0013837.
• [3] Pathway, in silico and tissue-specific expression quantitative analyses of oesophageal squamous cell carcinoma genome-wide association studies data.Int J Epidemiol. 2016 Feb;45(1):206-20. doi: 10.1093/ije/dyv294. Epub 2015 Dec 3.
• [4] Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau Pathology.Front Mol Neurosci. 2017 Mar 17;10:69. doi: 10.3389/fnmol.2017.00069. eCollection 2017.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [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] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [10] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] 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.
• [13] 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.