Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7MR9LY)

• DOT Name: tRNA-splicing endonuclease subunit Sen54 (TSEN54)
• Synonyms: SEN54 homolog; HsSEN54; tRNA-intron endonuclease Sen54
• Gene Name: TSEN54
• Related Disease:
  Intellectual disability
  Microlissencephaly
  Movement disorder
  Pontocerebellar hypoplasia type 2A
  Vision disorder
  Dystonia
  Hereditary ataxia
  Isolated congenital microcephaly
  Leukodystrophy
  Malignant glioma
  Pontocerebellar hypoplasia type 4
  Pontocerebellar hypoplasia type 5
  Neoplasm
  Pontocerebellar hypoplasia type 1A
  Pontocerebellar hypoplasia type 2
• UniProt ID: SEN54_HUMAN
• PDB ID: 7UXA; 7ZRZ; 8HMY; 8HMZ; 8ISS
• Pfam ID: PF12928
• Sequence:
  MEPEPEPAAVEVPAGRVLSARELFAARSRSQKLPQRSHGPKDFLPDGSAAQAERLRRCRE
  ELWQLLAEQRVERLGSLVAAEWRPEEGFVELKSPAGKFWQTMGFSEQGRQRLHPEEALYL
  LECGSIHLFHQDLPLSIQEAYQLLLTDHTVTFLQYQVFSHLKRLGYVVRRFQPSSVLSPY
  ERQLNLDASVQHLEDGDGKRKRSSSSPRSINKKAKALDNSLQPKSLAASSPPPCSQPSQC
  PEEKPQESSPMKGPGGPFQLLGSLGPSPGPAREGVGCSWESGRAENGVTGAGKRRWNFEQ
  ISFPNMASDSRHTLLRAPAPELLPANVAGRETDAESWCQKLNQRKEKLSRREREHHAEAA
  QFQEDVNADPEVQRCSSWREYKELLQRRQVQRSQRRAPHLWGQPVTPLLSPGQASSPAVV
  LQHISVLQTTHLPDGGARLLEKSGGLEIIFDVYQADAVATFRKNNPGKPYARMCISGFDE
  PVPDLCSLKRLSYQSGDVPLIFALVDHGDISFYSFRDFTLPQDVGH
• Function: Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA. It cleaves pre-tRNA at the 5' and 3' splice sites to release the intron. The products are an intron and two tRNA half-molecules bearing 2',3' cyclic phosphate and 5'-OH termini. There are no conserved sequences at the splice sites, but the intron is invariably located at the same site in the gene, placing the splice sites an invariant distance from the constant structural features of the tRNA body. The tRNA splicing endonuclease is also involved in mRNA processing via its association with pre-mRNA 3'-end processing factors, establishing a link between pre-tRNA splicing and pre-mRNA 3'-end formation, suggesting that the endonuclease subunits function in multiple RNA-processing events.
• Reactome Pathway: tRNA processing in the nucleus (R-HSA-6784531)
• BioCyc Pathway: MetaCyc:HS11953-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Microlissencephaly	DISUCKNT	Definitive	Biomarker	[1]
Movement disorder	DISOJJ2D	Definitive	Biomarker	[1]
Pontocerebellar hypoplasia type 2A	DISOFRJQ	Definitive	Autosomal recessive	[2]
Vision disorder	DIS8R6NJ	Definitive	Biomarker	[1]
Dystonia	DISJLFGW	Strong	Genetic Variation	[3]
Hereditary ataxia	DIS6JNI3	Strong	Genetic Variation	[4]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[1]
Leukodystrophy	DISVY1TT	Strong	Genetic Variation	[5]
Malignant glioma	DISFXKOV	Strong	Biomarker	[6]
Pontocerebellar hypoplasia type 4	DIS01OM1	Strong	Autosomal recessive	[1]
Pontocerebellar hypoplasia type 5	DISZ2FWT	Strong	Autosomal recessive	[7]
Neoplasm	DISZKGEW	moderate	Biomarker	[8]
Pontocerebellar hypoplasia type 1A	DIS7X0VS	moderate	GermlineCausalMutation	[9]
Pontocerebellar hypoplasia type 2	DISXV76G	Supportive	Autosomal recessive	[10]

4 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 tRNA-splicing endonuclease subunit Sen54 (TSEN54).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of tRNA-splicing endonuclease subunit Sen54 (TSEN54).	[12]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of tRNA-splicing endonuclease subunit Sen54 (TSEN54).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA-splicing endonuclease subunit Sen54 (TSEN54).	[16]

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 tRNA-splicing endonuclease subunit Sen54 (TSEN54).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of tRNA-splicing endonuclease subunit Sen54 (TSEN54).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of tRNA-splicing endonuclease subunit Sen54 (TSEN54).	[17]

References

• [1] tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet. 2008 Sep;40(9):1113-8. doi: 10.1038/ng.204.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.Brain. 2011 Jan;134(Pt 1):143-56. doi: 10.1093/brain/awq287. Epub 2010 Oct 15.
• [4] A familial lateonset hereditary ataxia mimicking pontocerebellar hypoplasia caused by a novel TSEN54 mutation.Mol Med Rep. 2014 Sep;10(3):1423-5. doi: 10.3892/mmr.2014.2342. Epub 2014 Jun 17.
• [5] TSEN54 missense variant in Standard Schnauzers with leukodystrophy.PLoS Genet. 2019 Oct 4;15(10):e1008411. doi: 10.1371/journal.pgen.1008411. eCollection 2019 Oct.
• [6] Overexpression of the orphan receptor Nur77 and its translocation induced by PCH4 may inhibit malignant glioma cell growth and induce cell apoptosis.J Surg Oncol. 2011 Apr;103(5):442-50. doi: 10.1002/jso.21809. Epub 2011 Jan 18.
• [7] Pontocerebellar hypoplasia type 2: a neuropathological update. Acta Neuropathol. 2007 Oct;114(4):373-86. doi: 10.1007/s00401-007-0263-0. Epub 2007 Jul 20.
• [8] Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma.Invest New Drugs. 2012 Feb;30(1):79-89. doi: 10.1007/s10637-010-9518-z. Epub 2010 Sep 1.
• [9] TSEN54 mutation in a child with pontocerebellar hypoplasia type 1.Acta Neuropathol. 2011 May;121(5):671-3. doi: 10.1007/s00401-011-0823-1. Epub 2011 Apr 6.
• [10] TSEN54 Pontocerebellar Hypoplasia. 2009 Sep 8 [updated 2020 May 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [15] 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.
• [16] 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.
• [17] 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.