Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIV69YA)

• DOT Name: Poly(A) polymerase gamma (PAPOLG)
• Synonyms: PAP-gamma; EC 2.7.7.19; Neo-poly(A) polymerase; Neo-PAP; Polynucleotide adenylyltransferase gamma; SRP RNA 3'-adenylating enzyme; Signal recognition particle RNA-adenylating enzyme; SRP RNA-adenylating enzyme
• Gene Name: PAPOLG
• Related Disease:
  Breast cancer
  Breast carcinoma
  Pyelonephritis
  Cervical carcinoma
  Systemic lupus erythematosus
• UniProt ID: PAPOG_HUMAN
• PDB ID: 4LT6
• EC Number: 2.7.7.19
• Pfam ID: PF04928 ; PF20750 ; PF04926
• Sequence:
  MKEMSANTVLDSQRQQKHYGITSPISLASPKEIDHIYTQKLIDAMKPFGVFEDEEELNHR
  LVVLGKLNNLVKEWISDVSESKNLPPSVVATVGGKIFTFGSYRLGVHTKGADIDALCVAP
  RHVERSDFFQSFFEKLKHQDGIRNLRAVEDAFVPVIKFEFDGIEIDLVFARLAIQTISDN
  LDLRDDSRLRSLDIRCIRSLNGCRVTDEILHLVPNKETFRLTLRAVKLWAKRRGIYSNML
  GFLGGVSWAMLVARTCQLYPNAAASTLVHKFFLVFSKWEWPNPVLLKQPEESNLNLPVWD
  PRVNPSDRYHLMPIITPAYPQQNSTYNVSTSTRTVMVEEFKQGLAVTDEILQGKSDWSKL
  LEPPNFFQKYRHYIVLTASASTEENHLEWVGLVESKIRVLVGNLERNEFITLAHVNPQSF
  PGNKEHHKDNNYVSMWFLGIIFRRVENAESVNIDLTYDIQSFTDTVYRQANNINMLKEGM
  KIEATHVKKKQLHHYLPAEILQKKKKQSLSDVNRSSGGLQSKRLSLDSSCLDSSRDTDNG
  TPFNSPASKSDSPSVGETERNSAEPAAVIVEKPLSVPPAQGLSIPVIGAKVDSTVKTVSP
  PTVCTIPTVVGRNVIPRITTPHNPAQGQPHLNGMSNITKTVTPKRSHSPSIDGTPKRLKD
  VEKFIRLESTFKDPRTAEERKRKSVDAIGGESMPIPTIDTSRKKRLPSKELPDSSSPVPA
  NNIRVIKNSIRLTLNR
• Function: Responsible for the post-transcriptional adenylation of the 3'-terminal of mRNA precursors and several small RNAs including signal recognition particle (SRP) RNA, nuclear 7SK RNA, U2 small nuclear RNA, and ribosomal 5S RNA.
• Tissue Specificity: Expressed predominantly in testis, and weakly in other tissues. Overexpressed in several tumors.
• KEGG Pathway: mR. surveillance pathway (hsa03015)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Pyelonephritis	DISAOX93	Strong	Genetic Variation	[2]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[3]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Poly(A) polymerase gamma (PAPOLG).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Poly(A) polymerase gamma (PAPOLG).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Poly(A) polymerase gamma (PAPOLG).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Poly(A) polymerase gamma (PAPOLG).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Poly(A) polymerase gamma (PAPOLG).	[9]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Poly(A) polymerase gamma (PAPOLG).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Poly(A) polymerase gamma (PAPOLG).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Poly(A) polymerase gamma (PAPOLG).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Poly(A) polymerase gamma (PAPOLG).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Poly(A) polymerase gamma (PAPOLG).	[16]

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 Poly(A) polymerase gamma (PAPOLG).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Poly(A) polymerase gamma (PAPOLG).	[13]

References

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• [2] Gene products specifying adhesion of uropathogenic Escherichia coli are minor components of pili.Proc Natl Acad Sci U S A. 1986 Mar;83(6):1891-5. doi: 10.1073/pnas.83.6.1891.
• [3] New approach to human high-risk papillomavirus (HR-HPV) genotyping.Neoplasma. 2002;49(4):217-24.
• [4] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.