Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0KSON1)

• DOT Name: Ubiquitin carboxyl-terminal hydrolase 45
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme 45; Ubiquitin thioesterase 45; Ubiquitin-specific-processing protease 45
• Gene Name: USP45
• Related Disease:
  Leber congenital amaurosis 9
  Leber congenital amaurosis
  Leber congenital amaurosis 19
• UniProt ID: UBP45_HUMAN
• EC Number: 3.4.19.12
• Pfam ID: PF00443 ; PF02148
• Sequence:
  MRVKDPTKALPEKAKRSKRPTVPHDEDSSDDIAVGLTCQHVSHAISVNHVKRAIAENLWS
  VCSECLKERRFYDGQLVLTSDIWLCLKCGFQGCGKNSESQHSLKHFKSSRTEPHCIIINL
  STWIIWCYECDEKLSTHCNKKVLAQIVDFLQKHASKTQTSAFSRIMKLCEEKCETDEIQK
  GGKCRNLSVRGITNLGNTCFFNAVMQNLAQTYTLTDLMNEIKESSTKLKIFPSSDSQLDP
  LVVELSRPGPLTSALFLFLHSMKETEKGPLSPKVLFNQLCQKAPRFKDFQQQDSQELLHY
  LLDAVRTEETKRIQASILKAFNNPTTKTADDETRKKVKAYGKEGVKMNFIDRIFIGELTS
  TVMCEECANISTVKDPFIDISLPIIEERVSKPLLWGRMNKYRSLRETDHDRYSGNVTIEN
  IHQPRAAKKHSSSKDKSQLIHDRKCIRKLSSGETVTYQKNENLEMNGDSLMFASLMNSES
  RLNESPTDDSEKEASHSESNVDADSEPSESESASKQTGLFRSSSGSGVQPDGPLYPLSAG
  KLLYTKETDSGDKEMAEAISELRLSSTVTGDQDFDRENQPLNISNNLCFLEGKHLRSYSP
  QNAFQTLSQSYITTSKECSIQSCLYQFTSMELLMGNNKLLCENCTKNKQKYQEETSFAEK
  KVEGVYTNARKQLLISAVPAVLILHLKRFHQAGLSLRKVNRHVDFPLMLDLAPFCSATCK
  NASVGDKVLYGLYGIVEHSGSMREGHYTAYVKVRTPSRKLSEHNTKKKNVPGLKAADNES
  AGQWVHVSDTYLQVVPESRALSAQAYLLFYERVL
• Function: Catalyzes the deubiquitination of SPDL1. Plays a role in the repair of UV-induced DNA damage via deubiquitination of ERCC1, promoting its recruitment to DNA damage sites. May be involved in the maintenance of photoreceptor function. May play a role in normal retinal development. Plays a role in cell migration.
• Tissue Specificity: Widely expressed. High expression is detected in the cerebellum. In the eye, it is expressed at high levels in the optic nerve, sclera and retina, with relatively low levels in the choroid, lens and retinal pigment epithelium .
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: Formation of Incision Complex in GG-NER (R-HSA-5696395)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leber congenital amaurosis 9	DIS35YGW	Strong	Autosomal recessive	[1]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[1]
Leber congenital amaurosis 19	DISN4ZQ8	Limited	Unknown	[1]

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 Ubiquitin carboxyl-terminal hydrolase 45.	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ubiquitin carboxyl-terminal hydrolase 45.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[8]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[13]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Ubiquitin carboxyl-terminal hydrolase 45.	[14]

References

• [1] Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis. J Med Genet. 2019 May;56(5):325-331. doi: 10.1136/jmedgenet-2018-105709. Epub 2018 Dec 20.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] 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.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [14] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.