Details of Drug Off-Target (DOT)

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

• DOT Name: RNA polymerase II-associated factor 1 homolog (PAF1)
• Synonyms: hPAF1; Pancreatic differentiation protein 2
• Gene Name: PAF1
• Related Disease:
  Acute myelogenous leukaemia
  Breast adenocarcinoma
  Breast cancer
  Breast carcinoma
  Colon carcinoma
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Peroxisomal disorder
  Prostate adenocarcinoma
  Wilms tumor
  Zika virus infection
  Hyperparathyroidism 2 with jaw tumors
  Peroxisome biogenesis disorder
  Advanced cancer
  Colorectal carcinoma
  Pancreatic cancer
  Zellweger spectrum disorders
• UniProt ID: PAF1_HUMAN
• PDB ID: 4M6T; 5ZYQ; 6GMH; 6TED; 7OOP; 7OPC; 7OPD; 7UNC; 7UND
• Pfam ID: PF03985
• Sequence:
  MAPTIQTQAQREDGHRPNSHRTLPERSGVVCRVKYCNSLPDIPFDPKFITYPFDQNRFVQ
  YKATSLEKQHKHDLLTEPDLGVTIDLINPDTYRIDPNVLLDPADEKLLEEEIQAPTSSKR
  SQQHAKVVPWMRKTEYISTEFNRYGISNEKPEVKIGVSVKQQFTEEEIYKDRDSQITAIE
  KTFEDAQKSISQHYSKPRVTPVEVMPVFPDFKMWINPCAQVIFDSDPAPKDTSGAAALEM
  MSQAMIRGMMDEEGNQFVAYFLPVEETLKKRKRDQEEEMDYAPDDVYDYKIAREYNWNVK
  NKASKGYEENYFFIFREGDGVYYNELETRVRLSKRRAKAGVQSGTNALLVVKHRDMNEKE
  LEAQEARKAQLENHEPEEEEEEEMETEEKEAGGSDEEQEKGSSSEKEGSEDEHSGSESER
  EEGDRDEASDKSGSGEDESSEDEARAARDKEEIFGSDADSEDDADSDDEDRGQAQGGSDN
  DSDSGSNGGGQRSRSHSRSASPFPSGSEHSAQEDGSEAAASDSSEADSDSD
• Function: Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Connects PAF1C with the RNF20/40 E3 ubiquitin-protein ligase complex. Involved in polyadenylation of mRNA precursors. Has oncogenic activity in vivo and in vitro.
• Reactome Pathway:
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Posttranslational Modification	[1]
Breast adenocarcinoma	DISMPHJ0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[4]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[4]
Peroxisomal disorder	DISV185U	Strong	Biomarker	[8]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[2]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[9]
Zika virus infection	DISQUCTY	Strong	Biomarker	[10]
Hyperparathyroidism 2 with jaw tumors	DISWEGI1	moderate	Altered Expression	[11]
Peroxisome biogenesis disorder	DISBQ6QJ	Disputed	Biomarker	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[14]
Pancreatic cancer	DISJC981	Limited	Posttranslational Modification	[15]
Zellweger spectrum disorders	DISW52CE	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of RNA polymerase II-associated factor 1 homolog (PAF1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RNA polymerase II-associated factor 1 homolog (PAF1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RNA polymerase II-associated factor 1 homolog (PAF1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA polymerase II-associated factor 1 homolog (PAF1).	[20]
Marinol	DM70IK5	Approved	Marinol increases the expression of RNA polymerase II-associated factor 1 homolog (PAF1).	[21]

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 RNA polymerase II-associated factor 1 homolog (PAF1).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of RNA polymerase II-associated factor 1 homolog (PAF1).	[23]

References

• [1] PAF1 complex interactions with SETDB1 mediate promoter H3K9 methylation and transcriptional repression of Hoxa9 and Meis1 in acute myeloid leukemia.Oncotarget. 2018 Apr 24;9(31):22123-22136. doi: 10.18632/oncotarget.25204. eCollection 2018 Apr 24.
• [2] New platinum (II) and palladium (II) complexes of coumarin-thiazole Schiff base with a fluorescent chemosensor properties: Synthesis, spectroscopic characterization, X-ray structure determination, in vitro anticancer activity on various human carcinoma cell lines and computational studies.J Photochem Photobiol B. 2018 Jan;178:428-439. doi: 10.1016/j.jphotobiol.2017.11.030. Epub 2017 Nov 22.
• [3] Anticancer Activity and Cisplatin Binding Ability of Bis-Quinoline and Bis-Isoquinoline Derived [Pd(2)L(4)](4+) Metallosupramolecular Cages.Front Chem. 2018 Nov 22;6:563. doi: 10.3389/fchem.2018.00563. eCollection 2018.
• [4] hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells.Oncotarget. 2017 Feb 28;8(9):14806-14820. doi: 10.18632/oncotarget.14775.
• [5] Novel Pd(II)-salen complexes showing high in vitro anti-proliferative effects against human hepatoma cancer by modulating specific regulatory genes.Dalton Trans. 2012 Sep 21;41(35):10854-64. doi: 10.1039/c2dt31143g. Epub 2012 Aug 3.
• [6] Cigarette Smoke Induces Stem Cell Features of Pancreatic Cancer Cells via PAF1.Gastroenterology. 2018 Sep;155(3):892-908.e6. doi: 10.1053/j.gastro.2018.05.041. Epub 2018 Jun 2.
• [7] Pt(II) and Pd(II) complexes with a thiazoline derivative ligand: Synthesis, structural characterization, antiproliferative activity and evaluation of pro-apoptotic ability in tumor cell lines HT-29 and U-937.J Inorg Biochem. 2020 Jan;202:110870. doi: 10.1016/j.jinorgbio.2019.110870. Epub 2019 Oct 22.
• [8] The Pichia pastoris PER6 gene product is a peroxisomal integral membrane protein essential for peroxisome biogenesis and has sequence similarity to the Zellweger syndrome protein PAF-1.Mol Cell Biol. 1996 May;16(5):2527-36. doi: 10.1128/MCB.16.5.2527.
• [9] Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour.Nat Commun. 2014 Aug 7;5:4398. doi: 10.1038/ncomms5398.
• [10] Analysis of the Zika and Japanese Encephalitis Virus NS5 Interactomes.J Proteome Res. 2019 Aug 2;18(8):3203-3218. doi: 10.1021/acs.jproteome.9b00318. Epub 2019 Jun 27.
• [11] Defective nucleolar localization and dominant interfering properties of a parafibromin L95P missense mutant causing the hyperparathyroidism-jaw tumor syndrome.Endocr Relat Cancer. 2010 May 18;17(2):513-24. doi: 10.1677/ERC-09-0272. Print 2010 Jun.
• [12] From expressed sequence tags to peroxisome biogenesis disorder genes.Ann N Y Acad Sci. 1996 Dec 27;804:516-23. doi: 10.1111/j.1749-6632.1996.tb18641.x.
• [13] Cis and trans interactions between genes encoding PAF1 complex and ESCRT machinery components in yeast.Curr Genet. 2018 Oct;64(5):1105-1116. doi: 10.1007/s00294-018-0828-6. Epub 2018 Mar 22.
• [14] Biological evaluations of newly-designed Pt(II) and Pd(II) complexes using spectroscopic and molecular docking approaches.J Biomol Struct Dyn. 2019 Aug;37(13):3422-3433. doi: 10.1080/07391102.2018.1516164. Epub 2018 Nov 1.
• [15] Human RNA polymerase II-association factor 1 (hPaf1/PD2) regulates histone methylation and chromatin remodeling in pancreatic cancer.PLoS One. 2011;6(10):e26926. doi: 10.1371/journal.pone.0026926. Epub 2011 Oct 27.
• [16] A nonmammalian homolog of the PAF1 gene (Zellweger syndrome) discovered as a gene involved in caryogamy in the fungus Podospora anserina.Cell. 1995 Jun 30;81(7):1043-51. doi: 10.1016/s0092-8674(05)80009-1.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 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.
• [21] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [22] 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.
• [23] 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.