Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG90DYF)

• DOT Name: Poly(U)-binding-splicing factor PUF60 (PUF60)
• Synonyms: 60 kDa poly(U)-binding-splicing factor; FUSE-binding protein-interacting repressor; FBP-interacting repressor; Ro-binding protein 1; RoBP1; Siah-binding protein 1; Siah-BP1
• Gene Name: PUF60
• Related Disease:
  8q24.3 microdeletion syndrome
  Syndromic intellectual disability
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Head-neck squamous cell carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Idiopathic inflammatory myopathy
  Malignant pleural mesothelioma
  Mesothelioma
  Myositis disease
  Myotonic dystrophy type 1
  Polymyositis
  Rheumatoid arthritis
  Sweetener
  Synovial sarcoma
  Systemic lupus erythematosus
  Trichohepatoenteric syndrome
  Type-1/2 diabetes
  Esophageal cancer
  Isolated congenital microcephaly
  Non-small-cell lung cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Dermatomyositis
  Esophageal squamous cell carcinoma
  Intellectual disability
  Metastatic malignant neoplasm
  Neoplasm
  Neoplasm of esophagus
  Sjogren syndrome
• UniProt ID: PUF60_HUMAN
• PDB ID: 2DNY; 2KXF; 2KXH; 2QFJ; 3DXB; 3UE2; 3US5; 3UWT; 5KVY; 5KW1; 5KW6; 5KWQ; 6LUR; 6SLO; 7Q8A; 7Z3X
• Pfam ID: PF00076
• Sequence:
  MATATIALQVNGQQGGGSEPAAAAAVVAAGDKWKPPQGTDSIKMENGQSTAAKLGLPPLT
  PEQQEALQKAKKYAMEQSIKSVLVKQTIAHQQQQLTNLQMAAVTMGFGDPLSPLQSMAAQ
  RQRALAIMCRVYVGSIYYELGEDTIRQAFAPFGPIKSIDMSWDSVTMKHKGFAFVEYEVP
  EAAQLALEQMNSVMLGGRNIKVGRPSNIGQAQPIIDQLAEEARAFNRIYVASVHQDLSDD
  DIKSVFEAFGKIKSCTLARDPTTGKHKGYGFIEYEKAQSSQDAVSSMNLFDLGGQYLRVG
  KAVTPPMPLLTPATPGGLPPAAAVAAAAATAKITAQEAVAGAAVLGTLGTPGLVSPALTL
  AQPLGTLPQAVMAAQAPGVITGVTPARPPIPVTIPSVGVVNPILASPPTLGLLEPKKEKE
  EEELFPESERPEMLSEQEHMSISGSSARHMVMQKLLRKQESTVMVLRNMVDPKDIDDDLE
  GEVTEECGKFGAVNRVIIYQEKQGEEEDAEIIVKIFVEFSIASETHKAIQALNGRWFAGR
  KVVAEVYDQERFDNSDLSA
• Function: DNA- and RNA-binding protein, involved in several nuclear processes such as pre-mRNA splicing, apoptosis and transcription regulation. In association with FUBP1 regulates MYC transcription at the P2 promoter through the core-TFIIH basal transcription factor. Acts as a transcriptional repressor through the core-TFIIH basal transcription factor. Represses FUBP1-induced transcriptional activation but not basal transcription. Decreases ERCC3 helicase activity. Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells. Is also involved in pre-mRNA splicing. Promotes splicing of an intron with weak 3'-splice site and pyrimidine tract in a cooperative manner with U2AF2. Involved in apoptosis induction when overexpressed in HeLa cells. Isoform 6 failed to repress MYC transcription and inhibited FIR-induced apoptosis in colorectal cancer. Isoform 6 may contribute to tumor progression by enabling increased MYC expression and greater resistance to apoptosis in tumors than in normal cells. Modulates alternative splicing of several mRNAs. Binds to relaxed DNA of active promoter regions. Binds to the pyrimidine tract and 3'-splice site regions of pre-mRNA; binding is enhanced in presence of U2AF2. Binds to Y5 RNA in association with RO60. Binds to poly(U) RNA.
• Tissue Specificity: Isoform 2 is expressed in colonic epithelium and colorectal epithelium cancer (at protein level). Isoform 6 is expressed in colorectal epithelial cancer but below detection level in colonic epithelium. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
8q24.3 microdeletion syndrome	DISI3CFH	Definitive	Autosomal dominant	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[6]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[8]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[9]
Malignant pleural mesothelioma	DIST2R60	Strong	Biomarker	[10]
Mesothelioma	DISKWK9M	Strong	Therapeutic	[10]
Myositis disease	DISCIXF0	Strong	Biomarker	[9]
Myotonic dystrophy type 1	DISJC0OX	Strong	Biomarker	[9]
Polymyositis	DIS5DHFP	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[9]
Sweetener	DISDGALM	Strong	Biomarker	[9]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[9]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[9]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[11]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[9]
Esophageal cancer	DISGB2VN	moderate	Altered Expression	[3]
Isolated congenital microcephaly	DISUXHZ6	Disputed	Genetic Variation	[12]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Biomarker	[13]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[14]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[14]
Carcinoma of esophagus	DISS6G4D	Limited	Biomarker	[15]
Dermatomyositis	DIS50C5O	Limited	Biomarker	[16]
Esophageal squamous cell carcinoma	DIS5N2GV	Limited	Biomarker	[16]
Intellectual disability	DISMBNXP	Limited	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[3]
Neoplasm	DISZKGEW	Limited	Altered Expression	[14]
Neoplasm of esophagus	DISOLKAQ	Limited	Biomarker	[15]
Sjogren syndrome	DISUBX7H	Limited	Biomarker	[16]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Poly(U)-binding-splicing factor PUF60 (PUF60) increases the response to substance of Cisplatin.	[10]

11 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 Poly(U)-binding-splicing factor PUF60 (PUF60).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[24]
Selenium	DM25CGV	Approved	Selenium increases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[25]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[26]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[27]
Epanova	DMHEAGL	Approved	Epanova increases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[28]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Poly(U)-binding-splicing factor PUF60 (PUF60).	[25]

3 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 Poly(U)-binding-splicing factor PUF60 (PUF60).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Poly(U)-binding-splicing factor PUF60 (PUF60).	[29]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Poly(U)-binding-splicing factor PUF60 (PUF60).	[30]

References

• [1] Eye coloboma and complex cardiac malformations belong to the clinical spectrum of PUF60 variants. Clin Genet. 2017 Sep;92(3):350-351. doi: 10.1111/cge.12965. Epub 2017 Mar 30.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Disturbed alternative splicing of FIR (PUF60) directed cyclin E overexpression in esophageal cancers.Oncotarget. 2018 May 1;9(33):22929-22944. doi: 10.18632/oncotarget.25149. eCollection 2018 May 1.
• [4] Identification of specific and common diagnostic antibody markers for gastrointestinal cancers by SEREX screening using testis cDNA phage library.Oncotarget. 2018 Jan 1;9(26):18559-18569. doi: 10.18632/oncotarget.24963. eCollection 2018 Apr 6.
• [5] Interactions between SAP155 and FUSE-binding protein-interacting repressor bridges c-Myc and P27Kip1 expression.Mol Cancer Res. 2013 Jul;11(7):689-98. doi: 10.1158/1541-7786.MCR-12-0673. Epub 2013 Apr 17.
• [6] Sendai virus-mediated gene transfer of the c-myc suppressor far-upstream element-binding protein-interacting repressor suppresses head and neck cancer.Gene Ther. 2015 Apr;22(4):297-304. doi: 10.1038/gt.2014.123. Epub 2015 Jan 15.
• [7] Involvement of PUF60 in Transcriptional and Post-transcriptional Regulation of Hepatitis B Virus Pregenomic RNA Expression.Sci Rep. 2017 Oct 9;7(1):12874. doi: 10.1038/s41598-017-12497-y.
• [8] Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma.Hepatology. 2014 Oct;60(4):1241-50. doi: 10.1002/hep.27218. Epub 2014 Jul 31.
• [9] The prevalence and clinical significance of anti-PUF60 antibodies in patients with idiopathic inflammatory myopathy.Clin Rheumatol. 2018 Jun;37(6):1573-1580. doi: 10.1007/s10067-018-4031-4. Epub 2018 Mar 15.
• [10] Synergistic effect of non-transmissible Sendai virus vector encoding the c-myc suppressor FUSE-binding protein-interacting repressor plus cisplatin in the treatment of malignant pleural mesothelioma. Cancer Sci. 2011 Jul;102(7):1366-73. doi: 10.1111/j.1349-7006.2011.01931.x. Epub 2011 May 9.
• [11] PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.Eur J Hum Genet. 2017 May;25(5):552-559. doi: 10.1038/ejhg.2017.27. Epub 2017 Mar 22.
• [12] PUF60-SCRIB fusion transcript in a patient with 8q24.3 microdeletion and atypical Verheij syndrome.Eur J Med Genet. 2019 Dec;62(12):103587. doi: 10.1016/j.ejmg.2018.11.021. Epub 2018 Nov 23.
• [13] Baseline tumor size and survival outcomes in lung cancer patients treated with immune checkpoint inhibitors.Semin Oncol. 2019 Aug-Oct;46(4-5):380-384. doi: 10.1053/j.seminoncol.2019.10.002. Epub 2019 Nov 6.
• [14] PUF60 accelerates the progression of breast cancer through downregulation of PTEN expression.Cancer Manag Res. 2019 Jan 17;11:821-830. doi: 10.2147/CMAR.S180242. eCollection 2019.
• [15] Adenovirus-mediated FIR demonstrated TP53-independent cell-killing effect and enhanced antitumor activity of carbon-ion beams.Gene Ther. 2016 Jan;23(1):50-6. doi: 10.1038/gt.2015.84. Epub 2015 Aug 4.
• [16] Anti-FIRexon2, a splicing variant form of PUF60, autoantibody is detected in the sera of esophageal squamous cell carcinoma.Cancer Sci. 2019 Jun;110(6):2004-2013. doi: 10.1111/cas.14024. Epub 2019 May 20.
• [17] Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability.Am J Med Genet B Neuropsychiatr Genet. 2018 Jan;177(1):10-20. doi: 10.1002/ajmg.b.32574. Epub 2017 Oct 9.
• [18] 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.
• [19] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [20] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [21] 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.
• [22] 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.
• [23] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [24] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [25] 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.
• [26] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [27] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [28] Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat. 2007 Jan;101(1):7-16. doi: 10.1007/s10549-006-9269-x. Epub 2006 Jul 6.
• [29] 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.
• [30] 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.
• [31] Synergistic effect of non-transmissible Sendai virus vector encoding the c-myc suppressor FUSE-binding protein-interacting repressor plus cisplatin in the treatment of malignant pleural mesothelioma. Cancer Sci. 2011 Jul;102(7):1366-73. doi: 10.1111/j.1349-7006.2011.01931.x. Epub 2011 May 9.