Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVAJOH3)

• DOT Name: U3 small nucleolar RNA-associated protein 4 homolog
• Synonyms: Cirhin; UTP4 small subunit processome component
• Gene Name: UTP4
• Related Disease:
  Hereditary North American Indian childhood cirrhosis
  Cirrhosis, familial
• UniProt ID: UTP4_HUMAN
• PDB ID: 7MQ8; 7MQ9; 7MQA
• Pfam ID: PF00400
• Sequence:
  MGEFKVHRVRFFNYVPSGIRCVAYNNQSNRLAVSRTDGTVEIYNLSANYFQEKFFPGHES
  RATEALCWAEGQRLFSAGLNGEIMEYDLQALNIKYAMDAFGGPIWSMAASPSGSQLLVGC
  EDGSVKLFQITPDKIQFERNFDRQKSRILSLSWHPSGTHIAAGSIDYISVFDVKSGSAVH
  KMIVDRQYMGVSKRKCIVWGVAFLSDGTIISVDSAGKVQFWDSATGTLVKSHLIANADVQ
  SIAVADQEDSFVVGTAEGTVFHFQLVPVTSNSSEKQWVRTKPFQHHTHDVRTVAHSPTAL
  ISGGTDTHLVFRPLMEKVEVKNYDAALRKITFPHRCLISCSKKRQLLLFQFAHHLELWRL
  GSTVATGKNGDTLPLSKNADHLLHLKTKGPENIICSCISPCGSWIAYSTVSRFFLYRLNY
  EHDNISLKRVSKMPAFLRSALQILFSEDSTKLFVASNQGALHIVQLSGGSFKHLHAFQPQ
  SGTVEAMCLLAVSPDGNWLAASGTSAGVHVYNVKQLKLHCTVPAYNFPVTAMAIAPNTNN
  LVIAHSDQQVFEYSIPDKQYTDWSRTVQKQGFHHLWLQRDTPITHISFHPKRPMHILLHD
  AYMFCIIDKSLPLPNDKTLLYNPFPPTNESDVIRRRTAHAFKISKIYKPLLFMDLLDERT
  LVAVERPLDDIIAQLPPPIKKKKFGT
• Function: Ribosome biogenesis factor. Involved in nucleolar processing of pre-18S ribosomal RNA. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted d Involved in SSU pre-rRNA processing at sites A', A0, 1 and 2b. Required for optimal pre-ribosomal RNA transcription by RNA polymerase. May be a transcriptional regulator ; (Microbial infection) Acts as a positive regulator of HIVEP1 which specifically binds to the DNA sequence 5'-GGGACTTTCC-3' found in enhancer elements of numerous viral promoters such as those of HIV-1, SV40, or CMV.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary North American Indian childhood cirrhosis	DISBJ6T5	Supportive	Autosomal recessive	[1]
Cirrhosis, familial	DISGG52B	Disputed	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of U3 small nucleolar RNA-associated protein 4 homolog.	[3]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of U3 small nucleolar RNA-associated protein 4 homolog.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[9]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of U3 small nucleolar RNA-associated protein 4 homolog.	[14]

References

• [1] A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. Am J Hum Genet. 2002 Dec;71(6):1443-9. doi: 10.1086/344580. Epub 2002 Nov 4.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] 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.
• [10] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.
• [13] 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.
• [14] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.