Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWO4UCJ)

• DOT Name: DNA polymerase delta catalytic subunit (POLD1)
• Synonyms: EC 2.7.7.7; 3'-5' exodeoxyribonuclease; EC 3.1.11.-; DNA polymerase subunit delta p125
• Gene Name: POLD1
• Related Disease:
  Colorectal neoplasm
  Endometrium neoplasm
  POLD1-related polyposis and colorectal cancer syndrome
  Advanced cancer
  Alzheimer disease
  B-cell lymphoma
  B-cell neoplasm
  Bladder cancer
  Breast neoplasm
  Carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal adenoma
  Colorectal cancer, susceptibility to, 10
  Endometrial cancer
  Endometrial carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Glioblastoma multiforme
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Herpes simplex infection
  Hypogonadism
  Hypogonadotropic hypogonadism
  Leukemia
  Lung cancer
  Lung carcinoma
  Mandibular hypoplasia-deafness-progeroid syndrome
  Retinoblastoma
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Epithelial ovarian cancer
  Metastatic malignant neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Polymerase proofreading-related adenomatous polyposis
  Adult glioblastoma
  Hereditary neoplastic syndrome
  Bone osteosarcoma
  Familial adenomatous polyposis
  Hereditary nonpolyposis colon cancer
  Lipodystrophy
  Lynch syndrome
  Melanoma
  Non-severe combined immunodeficiency due to polymerase delta deficiency
  Osteosarcoma
  Polyp of large intestine
  Rheumatoid arthritis
• UniProt ID: DPOD1_HUMAN
• PDB ID: 6S1M; 6S1N; 6S1O; 6TNY; 6TNZ
• EC Number: 2.7.7.7; 3.1.11.-
• Pfam ID: PF00136 ; PF03104 ; PF14260
• Sequence:
  MDGKRRPGPGPGVPPKRARGGLWDDDDAPRPSQFEEDLALMEEMEAEHRLQEQEEEELQS
  VLEGVADGQVPPSAIDPRWLRPTPPALDPQTEPLIFQQLEIDHYVGPAQPVPGGPPPSRG
  SVPVLRAFGVTDEGFSVCCHIHGFAPYFYTPAPPGFGPEHMGDLQRELNLAISRDSRGGR
  ELTGPAVLAVELCSRESMFGYHGHGPSPFLRITVALPRLVAPARRLLEQGIRVAGLGTPS
  FAPYEANVDFEIRFMVDTDIVGCNWLELPAGKYALRLKEKATQCQLEADVLWSDVVSHPP
  EGPWQRIAPLRVLSFDIECAGRKGIFPEPERDPVIQICSLGLRWGEPEPFLRLALTLRPC
  APILGAKVQSYEKEEDLLQAWSTFIRIMDPDVITGYNIQNFDLPYLISRAQTLKVQTFPF
  LGRVAGLCSNIRDSSFQSKQTGRRDTKVVSMVGRVQMDMLQVLLREYKLRSYTLNAVSFH
  FLGEQKEDVQHSIITDLQNGNDQTRRRLAVYCLKDAYLPLRLLERLMVLVNAVEMARVTG
  VPLSYLLSRGQQVKVVSQLLRQAMHEGLLMPVVKSEGGEDYTGATVIEPLKGYYDVPIAT
  LDFSSLYPSIMMAHNLCYTTLLRPGTAQKLGLTEDQFIRTPTGDEFVKTSVRKGLLPQIL
  ENLLSARKRAKAELAKETDPLRRQVLDGRQLALKVSANSVYGFTGAQVGKLPCLEISQSV
  TGFGRQMIEKTKQLVESKYTVENGYSTSAKVVYGDTDSVMCRFGVSSVAEAMALGREAAD
  WVSGHFPSPIRLEFEKVYFPYLLISKKRYAGLLFSSRPDAHDRMDCKGLEAVRRDNCPLV
  ANLVTASLRRLLIDRDPEGAVAHAQDVISDLLCNRIDISQLVITKELTRAASDYAGKQAH
  VELAERMRKRDPGSAPSLGDRVPYVIISAAKGVAAYMKSEDPLFVLEHSLPIDTQYYLEQ
  QLAKPLLRIFEPILGEGRAEAVLLRGDHTRCKTVLTGKVGGLLAFAKRRNCCIGCRTVLS
  HQGAVCEFCQPRESELYQKEVSHLNALEERFSRLWTQCQRCQGSLHEDVICTSRDCPIFY
  MRKKVRKDLEDQEQLLRRFGPPGPEAW
• Function: As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair. Exhibits both DNA polymerase and 3'- to 5'-exonuclease activities. Requires the presence of accessory proteins POLD2, POLD3 and POLD4 for full activity. Depending upon the absence (Pol-delta3) or the presence of POLD4 (Pol-delta4), displays differences in catalytic activity. Most notably, expresses higher proofreading activity in the context of Pol-delta3 compared with that of Pol-delta4. Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may 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, in the presence of POLD3 and POLD4, may catalyze the repair of broken replication forks through break-induced replication (BIR). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine, 8oxoG or abasic sites.
• Tissue Specificity: Widely expressed, with high levels of expression in heart and lung.
• 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)
  Cytosolic iron-sulfur cluster assembly (R-HSA-2564830)
  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

51 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal neoplasm	DISR1UCN	Definitive	Biomarker	[1]
Endometrium neoplasm	DIS6OS2L	Definitive	Biomarker	[1]
POLD1-related polyposis and colorectal cancer syndrome	DISVHTY7	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
B-cell neoplasm	DISVY326	Strong	Biomarker	[6]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[7]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[8]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[9]
Colon cancer	DISVC52G	Strong	Altered Expression	[10]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[10]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[11]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Autosomal dominant	[12]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[13]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[14]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Altered Expression	[15]
Fanconi's anemia	DISGW6Q8	Strong	Altered Expression	[15]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[16]
Glioma	DIS5RPEH	Strong	Altered Expression	[17]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[18]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[19]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[20]
Hypogonadism	DISICMNI	Strong	Biomarker	[21]
Hypogonadotropic hypogonadism	DIS8JSKR	Strong	Biomarker	[21]
Leukemia	DISNAKFL	Strong	Altered Expression	[22]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[3]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[3]
Mandibular hypoplasia-deafness-progeroid syndrome	DISERDZL	Strong	Autosomal dominant	[12]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[23]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[24]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[7]
Epithelial ovarian cancer	DIS56MH2	moderate	Genetic Variation	[25]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[26]
Ovarian cancer	DISZJHAP	moderate	Genetic Variation	[25]
Ovarian neoplasm	DISEAFTY	moderate	Genetic Variation	[25]
Pancreatic cancer	DISJC981	moderate	Biomarker	[27]
Polymerase proofreading-related adenomatous polyposis	DISGMJXH	Supportive	Autosomal dominant	[1]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[16]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	CausalMutation	[28]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[29]
Familial adenomatous polyposis	DISW53RE	Limited	Genetic Variation	[30]
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Genetic Variation	[31]
Lipodystrophy	DIS3SGVD	Limited	Genetic Variation	[32]
Lynch syndrome	DIS3IW5F	Limited	Genetic Variation	[31]
Melanoma	DIS1RRCY	Limited	Altered Expression	[33]
Non-severe combined immunodeficiency due to polymerase delta deficiency	DISQOWUX	Limited	Autosomal recessive	[2]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[29]
Polyp of large intestine	DISRE1MK	Limited	Genetic Variation	[11]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[34]

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 DNA polymerase delta catalytic subunit (POLD1).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA polymerase delta catalytic subunit (POLD1).	[39]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[40]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[41]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[41]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DNA polymerase delta catalytic subunit (POLD1).	[42]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[43]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[44]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[45]
Guanine	DMIWLJE	Phase 3	Guanine decreases the activity of DNA polymerase delta catalytic subunit (POLD1).	[46]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[47]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[49]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[50]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA polymerase delta catalytic subunit (POLD1).	[51]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of DNA polymerase delta catalytic subunit (POLD1).	[40]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of DNA polymerase delta catalytic subunit (POLD1).	[52]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of DNA polymerase delta catalytic subunit (POLD1).	[38]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DNA polymerase delta catalytic subunit (POLD1).	[48]

References

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