Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6JASZ1)

• DOT Name: Parafibromin (CDC73)
• Synonyms: Cell division cycle protein 73 homolog; Hyperparathyroidism 2 protein
• Gene Name: CDC73
• Related Disease:
  Acute myelogenous leukaemia
  Chronic kidney disease
  Familial primary hyperparathyroidism
  Head and neck carcinoma
  Hyperparathyroidism 2 with jaw tumors
  Adenoma
  Carcinoma
  Clear cell renal carcinoma
  Colon carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Familial adenomatous polyposis
  Familial hypocalciuric hypercalcemia 1
  Fibroma
  Hyperlipidemia
  Hyperparathyroidism
  Hyperparathyroidism 1
  Malignant tumor of parathyroid gland
  Multiple endocrine neoplasia
  Multiple endocrine neoplasia type 1
  Myocardial infarction
  Ovarian cancer
  Pancytopenia
  Papillary renal cell carcinoma
  Paraganglioma
  Parathyroid gland carcinoma
  Prostate cancer
  Prostate carcinoma
  Retinoblastoma
  Trichohepatoenteric syndrome
  Von hippel-lindau disease
  Wilms tumor
  Endometriosis
  Laryngeal disorder
  leukaemia
  Leukemia
  Lung cancer
  Primary hyperparathyroidism
  Squamous cell carcinoma
  Familial isolated hyperparathyroidism
  Adenocarcinoma
  Childhood kidney Wilms tumor
  Colorectal carcinoma
  Hereditary neoplastic syndrome
  Kidney neoplasm
  Polyp
• UniProt ID: CDC73_HUMAN
• PDB ID: 5YDE; 5YDF; 6TED; 7OOP; 7OPC; 7OPD; 7UNC; 7UND
• Pfam ID: PF05179 ; PF16050
• Sequence:
  MADVLSVLRQYNIQKKEIVVKGDEVIFGEFSWPKNVKTNYVVWGTGKEGQPREYYTLDSI
  LFLLNNVHLSHPVYVRRAATENIPVVRRPDRKDLLGYLNGEASTSASIDRSAPLEIGLQR
  STQVKRAADEVLAEAKKPRIEDEECVRLDKERLAARLEGHKEGIVQTEQIRSLSEAMSVE
  KIAAIKAKIMAKKRSTIKTDLDDDITALKQRSFVDAEVDVTRDIVSRERVWRTRTTILQS
  TGKNFSKNIFAILQSVKAREEGRAPEQRPAPNAAPVDPTLRTKQPIPAAYNRYDQERFKG
  KEETEGFKIDTMGTYHGMTLKSVTEGASARKTQTPAAQPVPRPVSQARPPPNQKKGSRTP
  IIIIPAATTSLITMLNAKDLLQDLKFVPSDEKKKQGCQRENETLIQRRKDQMQPGGTAIS
  VTVPYRVVDQPLKLMPQDWDRVVAVFVQGPAWQFKGWPWLLPDGSPVDIFAKIKAFHLKY
  DEVRLDPNVQKWDVTVLELSYHKRHLDRPVFLRFWETLDRYMVKHKSHLRF
• Function: Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways. May be involved in cell cycle progression through the regulation of cyclin D1/PRAD1 expression. 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 cleavage and polyadenylation specificity factor (CPSF) complex and the cleavage stimulation factor (CSTF) complex, and with Wnt signaling. Involved in polyadenylation of mRNA precursors.
• Tissue Specificity: Found in adrenal and parathyroid glands, kidney and heart.
• Reactome Pathway:
  Formation of the beta-catenin (R-HSA-201722)
  Hedgehog 'on' state (R-HSA-5632684)
  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

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Chronic kidney disease	DISW82R7	Definitive	Biomarker	[2]
Familial primary hyperparathyroidism	DIS6NA55	Definitive	Genetic Variation	[3]
Head and neck carcinoma	DISOU1DS	Definitive	Altered Expression	[4]
Hyperparathyroidism 2 with jaw tumors	DISWEGI1	Definitive	Autosomal dominant	[5]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[6]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[10]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[12]
Familial hypocalciuric hypercalcemia 1	DISPW6O5	Strong	Biomarker	[13]
Fibroma	DISH5078	Strong	Biomarker	[14]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[15]
Hyperparathyroidism	DIS4FVAT	Strong	Genetic Variation	[16]
Hyperparathyroidism 1	DISBI5VD	Strong	Autosomal dominant	[17]
Malignant tumor of parathyroid gland	DIS4X92K	Strong	Biomarker	[18]
Multiple endocrine neoplasia	DISZGBKW	Strong	Biomarker	[19]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Genetic Variation	[20]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[15]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[11]
Pancytopenia	DISVKEHV	Strong	Biomarker	[21]
Papillary renal cell carcinoma	DIS25HBV	Strong	Altered Expression	[8]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[22]
Parathyroid gland carcinoma	DISEER2W	Strong	Autosomal dominant	[23]
Prostate cancer	DISF190Y	Strong	Biomarker	[24]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[24]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[25]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[26]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Genetic Variation	[22]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[27]
Endometriosis	DISX1AG8	moderate	Genetic Variation	[28]
Laryngeal disorder	DISDKUQO	moderate	Altered Expression	[4]
leukaemia	DISS7D1V	moderate	Biomarker	[29]
Leukemia	DISNAKFL	moderate	Biomarker	[29]
Lung cancer	DISCM4YA	moderate	Altered Expression	[4]
Primary hyperparathyroidism	DISB4U1Q	moderate	Biomarker	[30]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[4]
Familial isolated hyperparathyroidism	DISC2Y84	Supportive	Autosomal dominant	[31]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[32]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Genetic Variation	[27]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[33]
Hereditary neoplastic syndrome	DISGXLG5	Limited	Genetic Variation	[34]
Kidney neoplasm	DISBNZTN	Limited	Genetic Variation	[27]
Polyp	DISRSLYF	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Parafibromin (CDC73).	[35]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Parafibromin (CDC73).	[36]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Parafibromin (CDC73).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Parafibromin (CDC73).	[38]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Parafibromin (CDC73).	[39]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Parafibromin (CDC73).	[40]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Parafibromin (CDC73).	[41]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Parafibromin (CDC73).	[42]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Parafibromin (CDC73).	[37]

3 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 Parafibromin (CDC73).	[43]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Parafibromin (CDC73).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Parafibromin (CDC73).	[45]

References

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• [3] Long-Term Outcomes of Parathyroidectomy in Hyperparathyroidism-Jaw Tumor Syndrome: Analysis of Five Families with CDC73 Mutations.World J Surg. 2020 Feb;44(2):508-516. doi: 10.1007/s00268-019-05156-y.
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• [21] The PAF1c Subunit CDC73 Is Required for Mouse Hematopoietic Stem Cell Maintenance but Displays Leukemia-Specific Gene Regulation.Stem Cell Reports. 2019 May 14;12(5):1069-1083. doi: 10.1016/j.stemcr.2019.03.010. Epub 2019 Apr 25.
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• [29] The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia.Oncogene. 2018 Jan 25;37(4):450-460. doi: 10.1038/onc.2017.337. Epub 2017 Sep 25.
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• [32] Parafibromin expression in lung normal tissue and carcinoma: its comparison with clinicopathological parameters of carcinoma.Histol Histopathol. 2011 Aug;26(8):1039-47. doi: 10.14670/HH-26.1039.
• [33] The in vitro and vivo effects of nuclear and cytosolic parafibromin expression on the aggressive phenotypes of colorectal cancer cells: a search of potential gene therapy target.Oncotarget. 2017 Apr 4;8(14):23603-23612. doi: 10.18632/oncotarget.15377.
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• [39] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
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• [43] 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.
• [44] 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.
• [45] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.