Details of Drug Off-Target (DOT)

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

• DOT Name: Inactive ubiquitin carboxyl-terminal hydrolase 53
• Synonyms: Inactive ubiquitin-specific peptidase 53
• Gene Name: USP53
• Related Disease:
  Cholestasis
  Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss
• UniProt ID: UBP53_HUMAN
• Pfam ID: PF00443
• Sequence:
  MAWVKFLRKPGGNLGKVYQPGSMLSLAPTKGLLNEPGQNSCFLNSAVQVLWQLDIFRRSL
  RVLTGHVCQGDACIFCALKTIFAQFQHSREKALPSDNIRHALAESFKDEQRFQLGLMDDA
  AECFENMLERIHFHIVPSRDADMCTSKSCITHQKFAMTLYEQCVCRSCGASSDPLPFTEF
  VRYISTTALCNEVERMLERHERFKPEMFAELLQAANTTDDYRKCPSNCGQKIKIRRVLMN
  CPEIVTIGLVWDSEHSDLTEAVVRNLATHLYLPGLFYRVTDENAKNSELNLVGMICYTSQ
  HYCAFAFHTKSSKWVFFDDANVKEIGTRWKDVVSKCIRCHFQPLLLFYANPDGTAVSTED
  ALRQVISWSHYKSVAENMGCEKPVIHKSDNLKENGFGDQAKQRENQKFPTDNISSSNRSH
  SHTGVGKGPAKLSHIDQREKIKDISRECALKAIEQKNLLSSQRKDLEKGQRKDLGRHRDL
  VDEDLSHFQSGSPPAPNGFKQHGNPHLYHSQGKGSYKHDRVVPQSRASAQIISSSKSQIL
  APGEKITGKVKSDNGTGYDTDSSQDSRDRGNSCDSSSKSRNRGWKPMRETLNVDSIFSES
  EKRQHSPRHKPNISNKPKSSKDPSFSNWPKENPKQKGLMTIYEDEMKQEIGSRSSLESNG
  KGAEKNKGLVEGKVHGDNWQMQRTESGYESSDHISNGSTNLDSPVIDGNGTVMDISGVKE
  TVCFSDQITTSNLNKERGDCTSLQSQHHLEGFRKELRNLEAGYKSHEFHPESHLQIKNHL
  IKRSHVHEDNGKLFPSSSLQIPKDHNAREHIHQSDEQKLEKPNECKFSEWLNIENSERTG
  LPFHVDNSASGKRVNSNEPSSLWSSHLRTVGLKPETAPLIQQQNIMDQCYFENSLSTECI
  IRSASRSDGCQMPKLFCQNLPPPLPPKKYAITSVPQSEKSESTPDVKLTEVFKATSHLPK
  HSLSTASEPSLEVSTHMNDERHKETFQVRECFGNTPNCPSSSSTNDFQANSGAIDAFCQP
  ELDSISTCPNETVSLTTYFSVDSCMTDTYRLKYHQRPKLSFPESSGFCNNSLS
• Function: Tight junction-associated protein that is involved in the survival of auditory hair cells and hearing. Maybe by modulating the barrier properties and mechanical stability of tight junctions. Has no peptidase activity.
• Tissue Specificity: Expressed predominantly in skeletal muscle and heart.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cholestasis	DISDJJWE	Strong	Autosomal recessive	[1]
Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss	DISBLK91	Strong	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[12]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[13]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[14]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[21]

2 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 affects the methylation of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Inactive ubiquitin carboxyl-terminal hydrolase 53.	[19]

References

• [1] 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.
• [2] New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin. J Hum Genet. 2021 Feb;66(2):151-159. doi: 10.1038/s10038-020-0811-1. Epub 2020 Aug 6.
• [3] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [4] 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.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [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 exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] 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.
• [11] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [14] 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.
• [15] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [19] 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.
• [20] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [21] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.