Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE5AQHJ)

• DOT Name: Pseudouridylate synthase 7 homolog (PUS7)
• Synonyms: EC 5.4.99.-
• Gene Name: PUS7
• Related Disease:
  Dyskeratosis congenita
  Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature
  Intellectual disability
  Isolated congenital microcephaly
  Syndromic intellectual disability
• UniProt ID: PUS7_HUMAN
• PDB ID: 5KKP
• EC Number: 5.4.99.-
• Pfam ID: PF01142
• Sequence:
  MEMTEMTGVSLKRGALVVEDNDSGVPVEETKKQKLSECSLTKGQDGLQNDFLSISEDVPR
  PPDTVSTGKGGKNSEAQLEDEEEEEEDGLSEECEEEESESFADMMKHGLTEADVGITKFV
  SSHQGFSGILKERYSDFVVHEIGKDGRISHLNDLSIPVDEEDPSEDIFTVLTAEEKQRLE
  ELQLFKNKETSVAIEVIEDTKEKRTIIHQAIKSLFPGLETKTEDREGKKYIVAYHAAGKK
  ALANPRKHSWPKSRGSYCHFVLYKENKDTMDAINVLSKYLRVKPNIFSYMGTKDKRAITV
  QEIAVLKITAQRLAHLNKCLMNFKLGNFSYQKNPLKLGELQGNHFTVVLRNITGTDDQVQ
  QAMNSLKEIGFINYYGMQRFGTTAVPTYQVGRAILQNSWTEVMDLILKPRSGAEKGYLVK
  CREEWAKTKDPTAALRKLPVKRCVEGQLLRGLSKYGMKNIVSAFGIIPRNNRLMYIHSYQ
  SYVWNNMVSKRIEDYGLKPVPGDLVLKGATATYIEEDDVNNYSIHDVVMPLPGFDVIYPK
  HKIQEAYREMLTADNLDIDNMRHKIRDYSLSGAYRKIIIRPQNVSWEVVAYDDPKIPLFN
  TDVDNLEGKTPPVFASEGKYRALKMDFSLPPSTYATMAIREVLKMDTSIKNQTQLNTTWL
  R
• Function: Pseudouridylate synthase that catalyzes pseudouridylation of RNAs. Acts as a regulator of protein synthesis in embryonic stem cells by mediating pseudouridylation of RNA fragments derived from tRNAs (tRFs): pseudouridylated tRFs inhibit translation by targeting the translation initiation complex. Also catalyzes pseudouridylation of mRNAs: mediates pseudouridylation of mRNAs with the consensus sequence 5'-UGUAG-3'. Acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at locations associated with alternatively spliced regions. Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3'-end processing. In addition to mRNAs and tRNAs, binds other types of RNAs, such as snRNAs, Y RNAs and vault RNAs, suggesting that it can catalyze pseudouridylation of many RNA types.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dyskeratosis congenita	DISSXV0K	Strong	Altered Expression	[1]
Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature	DISJS2FU	Strong	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[3]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Pseudouridylate synthase 7 homolog (PUS7).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pseudouridylate synthase 7 homolog (PUS7).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Pseudouridylate synthase 7 homolog (PUS7).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Pseudouridylate synthase 7 homolog (PUS7).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Pseudouridylate synthase 7 homolog (PUS7).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Pseudouridylate synthase 7 homolog (PUS7).	[13]
Busulfan	DMXYJ9C	Approved	Busulfan increases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pseudouridylate synthase 7 homolog (PUS7).	[21]

References

• [1] Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA.Cell. 2014 Sep 25;159(1):148-162. doi: 10.1016/j.cell.2014.08.028. Epub 2014 Sep 11.
• [2] Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol Psychiatry. 2017 Nov;22(11):1604-1614. doi: 10.1038/mp.2016.109. Epub 2016 Jul 26.
• [3] PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly. Hum Genet. 2019 Mar;138(3):231-239. doi: 10.1007/s00439-019-01980-3. Epub 2019 Feb 18.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] 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.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] 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.
• [14] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] 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.