Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG578YH)

• DOT Name: DNA polymerase delta subunit 4 (POLD4)
• Synonyms: DNA polymerase delta subunit p12
• Gene Name: POLD4
• Related Disease:
  Hyperglycemia
  Malaria
  Retinopathy
  Acute otitis media
  Adult respiratory distress syndrome
  Adult T-cell leukemia/lymphoma
  Bone osteosarcoma
  Cystic fibrosis
  Glioma
  Leukemia
  Neoplasm
  Non-hodgkin lymphoma
  Osteosarcoma
  Otitis media
  Pathologic nystagmus
  Rift valley fever
  Schizophrenia
  Small-cell lung cancer
  T-cell leukaemia
  Bloom syndrome
  Human T-lymphotropic virus 1 infectious disease
  Acute myelogenous leukaemia
  Adult glioblastoma
  Glioblastoma multiforme
  T-cell acute lymphoblastic leukaemia
• UniProt ID: DPOD4_HUMAN
• PDB ID: 6HVO; 6S1M; 6S1N; 6S1O; 6TNY; 6TNZ
• Pfam ID: PF04081
• Sequence:
  MGRKRLITDSYPVVKRREGPAGHSKGELAPELGEEPQPRDEEEAELELLRQFDLAWQYGP
  CTGITRLQRWCRAKQMGLEPPPEVWQVLKTHPGDPRFQCSLWHLYPL
• Function: As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair. Within this complex, increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3' to 5' exonuclease activity. Pol-delta4 participates in Okazaki fragment processing, through both the short flap pathway, as well as a nick translation system. Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb. Involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites. Its degradation in response to DNA damage is required for the inhibition of fork progression and cell survival.
• 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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperglycemia	DIS0BZB5	Definitive	Biomarker	[1]
Malaria	DISQ9Y50	Definitive	Biomarker	[2]
Retinopathy	DISB4B0F	Definitive	Biomarker	[3]
Acute otitis media	DISL8D8G	Strong	Biomarker	[4]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[5]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[6]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[7]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Altered Expression	[9]
Leukemia	DISNAKFL	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[12]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[7]
Otitis media	DISGZDUO	Strong	Biomarker	[4]
Pathologic nystagmus	DIS1QSPO	Strong	Biomarker	[13]
Rift valley fever	DISG6CM2	Strong	Genetic Variation	[14]
Schizophrenia	DISSRV2N	Strong	Biomarker	[15]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[16]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[17]
Bloom syndrome	DISKXQ7J	moderate	Altered Expression	[18]
Human T-lymphotropic virus 1 infectious disease	DISN5C4M	Disputed	Biomarker	[19]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[20]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[21]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[21]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Altered Expression	[22]

20 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 DNA polymerase delta subunit 4 (POLD4).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DNA polymerase delta subunit 4 (POLD4).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA polymerase delta subunit 4 (POLD4).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA polymerase delta subunit 4 (POLD4).	[26]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA polymerase delta subunit 4 (POLD4).	[27]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA polymerase delta subunit 4 (POLD4).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of DNA polymerase delta subunit 4 (POLD4).	[30]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA polymerase delta subunit 4 (POLD4).	[31]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA polymerase delta subunit 4 (POLD4).	[32]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DNA polymerase delta subunit 4 (POLD4).	[33]
Menadione	DMSJDTY	Approved	Menadione affects the expression of DNA polymerase delta subunit 4 (POLD4).	[32]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of DNA polymerase delta subunit 4 (POLD4).	[34]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of DNA polymerase delta subunit 4 (POLD4).	[35]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of DNA polymerase delta subunit 4 (POLD4).	[24]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of DNA polymerase delta subunit 4 (POLD4).	[36]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of DNA polymerase delta subunit 4 (POLD4).	[27]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of DNA polymerase delta subunit 4 (POLD4).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA polymerase delta subunit 4 (POLD4).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA polymerase delta subunit 4 (POLD4).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of DNA polymerase delta subunit 4 (POLD4).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of DNA polymerase delta subunit 4 (POLD4).	[28]

References

• [1] Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus.NMR Biomed. 2018 May;31(5):e3910. doi: 10.1002/nbm.3910. Epub 2018 Mar 13.
• [2] Low genetic diversity and functional constraint in loci encoding Plasmodium vivax P12 and P38 proteins in the Colombian population.Malar J. 2014 Feb 18;13:58. doi: 10.1186/1475-2875-13-58.
• [3] elemene inhibits oxygeninduced retinal neovascularization via promoting miR?7a and reducing VEGF expression.Mol Med Rep. 2019 Mar;19(3):2307-2316. doi: 10.3892/mmr.2019.9863. Epub 2019 Jan 15.
• [4] Pathological features in the LmnaDhe/+ mutant mouse provide a novel model of human otitis media and laminopathies.Am J Pathol. 2012 Sep;181(3):761-74. doi: 10.1016/j.ajpath.2012.05.031. Epub 2012 Jul 20.
• [5] Size-dependent anti-inflammatory activity of a peptide-gold nanoparticle hybrid in vitro and in a mouse model of acute lung injury.Acta Biomater. 2019 Feb;85:203-217. doi: 10.1016/j.actbio.2018.12.046. Epub 2018 Dec 28.
• [6] Palmitoylation and p8-mediated human T-cell leukemia virus type 1 transmission.J Virol. 2014 Feb;88(4):2319-22. doi: 10.1128/JVI.03444-13. Epub 2013 Nov 27.
• [7] Overexpression through amplification of genes in chromosome region 17p11.2 approximately p12 in high-grade osteosarcoma.Cancer Genet Cytogenet. 2004 Jul 1;152(1):8-14. doi: 10.1016/j.cancergencyto.2003.09.024.
• [8] Molecular characterization of pyocin S3, a novel S-type pyocin from Pseudomonas aeruginosa.J Biol Chem. 1995 Apr 14;270(15):8920-7. doi: 10.1074/jbc.270.15.8920.
• [9] TNF receptor-associated factor 6 regulates proliferation, apoptosis, and invasion of glioma cells.Mol Cell Biochem. 2013 May;377(1-2):87-96. doi: 10.1007/s11010-013-1573-2. Epub 2013 Jan 29.
• [10] The N-terminus of murine leukaemia virus p12 protein is required for mature core stability.PLoS Pathog. 2014 Oct 30;10(10):e1004474. doi: 10.1371/journal.ppat.1004474. eCollection 2014 Oct.
• [11] Loss of the p12 subunit of DNA polymerase delta leads to a defect in HR and sensitization to PARP inhibitors.DNA Repair (Amst). 2019 Jan;73:64-70. doi: 10.1016/j.dnarep.2018.11.003. Epub 2018 Nov 13.
• [12] Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas.Blood. 2002 Jun 1;99(11):4094-9. doi: 10.1182/blood.v99.11.4094.
• [13] Vestibular cerebellar evoked potentials in humans and their modulation during optokinetic stimulation.J Neurophysiol. 2018 Dec 1;120(6):3099-3109. doi: 10.1152/jn.00502.2018. Epub 2018 Oct 17.
• [14] Ability of a mutagenized virus variant to protect young lambs from Rift Valley fever.Am J Vet Res. 1991 Jan;52(1):50-5.
• [15] The cell cycle-related genes as biomarkers for schizophrenia.Prog Neuropsychopharmacol Biol Psychiatry. 2016 Oct 3;70:85-91. doi: 10.1016/j.pnpbp.2016.05.005. Epub 2016 May 20.
• [16] Regulation of DNA polymerase POLD4 influences genomic instability in lung cancer.Cancer Res. 2010 Nov 1;70(21):8407-16. doi: 10.1158/0008-5472.CAN-10-0784. Epub 2010 Sep 22.
• [17] Simian T cell leukemia virus type I from naturally infected feral monkeys from central and west Africa encodes a 91-amino acid p12 (ORF-I) protein as opposed to a 99-amino acid protein encoded by HTLV type I from humans.AIDS Res Hum Retroviruses. 1997 Mar 20;13(5):425-32. doi: 10.1089/aid.1997.13.425.
• [18] The Bloom's syndrome helicase (BLM) interacts physically and functionally with p12, the smallest subunit of human DNA polymerase delta.Nucleic Acids Res. 2008 Sep;36(16):5166-79. doi: 10.1093/nar/gkn498. Epub 2008 Aug 5.
• [19] Human T cell lymphotropic virus type I (HTLV-I) p12I is dispensable for HTLV-I transmission and maintenance of infection in vivo.AIDS Res Hum Retroviruses. 2004 Oct;20(10):1092-9. doi: 10.1089/aid.2004.20.1092.
• [20] The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene.Blood. 1995 Sep 15;86(6):2073-6.
• [21] Pharmacological effects of asiatic acid in glioblastoma cells under hypoxia.Mol Cell Biochem. 2017 Jun;430(1-2):179-190. doi: 10.1007/s11010-017-2965-5. Epub 2017 Feb 15.
• [22] Multipoint interphase FISH in childhood T-acute lymphoblastic leukemia detects subpopulations that carry different chromosome 3 aberrations.Cancer Genet Cytogenet. 2007 Jan 1;172(1):54-60. doi: 10.1016/j.cancergencyto.2006.08.004.
• [23] 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.
• [24] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [25] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [28] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [29] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [30] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [31] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [32] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [33] 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.
• [34] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [35] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [36] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [37] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [38] Identifying the Transcriptional Response of Cancer and Inflammation-Related Genes in Lung Cells in Relation to Ambient Air Chemical Mixtures in Houston, Texas. Environ Sci Technol. 2020 Nov 3;54(21):13807-13816. doi: 10.1021/acs.est.0c02250. Epub 2020 Oct 16.