Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT14UW31)

• DOT Name: tRNA-splicing endonuclease subunit Sen15 (TSEN15)
• Synonyms: SEN15 homolog; HsSEN15; tRNA-intron endonuclease Sen15
• Gene Name: TSEN15
• Related Disease:
  Isolated congenital microcephaly
  Pontocerebellar hypoplasia
  Pontocerebellar hypoplasia, type 2F
  Intellectual disability
  Venous thromboembolism
  Pontocerebellar hypoplasia type 2
• UniProt ID: SEN15_HUMAN
• PDB ID: 2GW6; 6Z9U; 7UXA; 7ZRZ; 8ISS
• Pfam ID: PF09631
• Sequence:
  MEERGDSEPTPGCSGLGPGGVRGFGDGGGAPSWAPEDAWMGTHPKYLEMMELDIGDATQV
  YVAFLVYLDLMESKSWHEVNCVGLPELQLICLVGTEIEGEGLQTVVPTPITASLSHNRIR
  EILKASRKLQGDPDLPMSFTLAIVESDSTIVYYKLTDGFMLPDPQNISLRR
• 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.
• Tissue Specificity: Widely expressed. Highly expressed in testis and uterus.
• Reactome Pathway: tRNA processing in the nucleus (R-HSA-6784531)
• BioCyc Pathway: MetaCyc:HS13020-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[1]
Pontocerebellar hypoplasia	DISRICMU	Strong	Biomarker	[1]
Pontocerebellar hypoplasia, type 2F	DISXK53W	Strong	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	moderate	Biomarker	[2]
Venous thromboembolism	DISUR7CR	moderate	Genetic Variation	[3]
Pontocerebellar hypoplasia type 2	DISXV76G	Supportive	Autosomal recessive	[1]

14 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 Sen15 (TSEN15).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of tRNA-splicing endonuclease subunit Sen15 (TSEN15).	[17]

References

• [1] Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly. Am J Hum Genet. 2016 Jul 7;99(1):228-35. doi: 10.1016/j.ajhg.2016.05.023.
• [2] Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015 Jan 13;10(2):148-61. doi: 10.1016/j.celrep.2014.12.015. Epub 2014 Dec 31.
• [3] A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis.BMC Med Genet. 2013 Mar 20;14:36. doi: 10.1186/1471-2350-14-36.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.