Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1UWYRI)

• DOT Name: tRNA-splicing endonuclease subunit Sen2 (TSEN2)
• Synonyms: EC 4.6.1.16; tRNA-intron endonuclease Sen2; HsSen2
• Gene Name: TSEN2
• Related Disease:
  Intellectual disability
  Isolated congenital microcephaly
  Microlissencephaly
  Movement disorder
  Vision disorder
  Non-insulin dependent diabetes
  Pontocerebellar hypoplasia type 2B
  Pontocerebellar hypoplasia type 2
• UniProt ID: SEN2_HUMAN
• PDB ID: 7UXA; 7ZRZ; 8HMY; 8HMZ; 8ISS
• EC Number: 4.6.1.16
• Pfam ID: PF01974 ; PF02778
• Sequence:
  MAEAVFHAPKRKRRVYETYESPLPIPFGQDHGPLKEFKIFRAEMINNNVIVRNAEDIEQL
  YGKGYFGKGILSRSRPSFTISDPKLVAKWKDMKTNMPIITSKRYQHSVEWAAELMRRQGQ
  DESTVRRILKDYTKPLEHPPVKRNEEAQVHDKLNSGMVSNMEGTAGGERPSVVNGDSGKS
  GGVGDPREPLGCLQEGSGCHPTTESFEKSVREDASPLPHVCCCKQDALILQRGLHHEDGS
  QHIGLLHPGDRGPDHEYVLVEEAECAMSEREAAPNEELVQRNRLICRRNPYRIFEYLQLS
  LEEAFFLVYALGCLSIYYEKEPLTIVKLWKAFTVVQPTFRTTYMAYHYFRSKGWVPKVGL
  KYGTDLLLYRKGPPFYHASYSVIIELVDDHFEGSLRRPLSWKSLAALSRVSVNVSKELML
  CYLIKPSTMTDKEMESPECMKRIKVQEVILSRWVSSRERSDQDDL
• Function: Constitutes one of the two 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. Isoform 1 probably carries the active site for 5'-splice site cleavage. 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. Isoform 2 is responsible for processing a yet unknown RNA substrate. The complex containing isoform 2 is not able to cleave pre-tRNAs properly, although it retains endonucleolytic activity.
• Tissue Specificity: Isoform 1 and isoform 2 are widely expressed at very low level.
• Reactome Pathway: tRNA processing in the nucleus (R-HSA-6784531)
• BioCyc Pathway: MetaCyc:HS08007-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Isolated congenital microcephaly	DISUXHZ6	Definitive	Biomarker	[1]
Microlissencephaly	DISUCKNT	Definitive	Biomarker	[1]
Movement disorder	DISOJJ2D	Definitive	Biomarker	[1]
Vision disorder	DIS8R6NJ	Definitive	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[2]
Pontocerebellar hypoplasia type 2B	DIS7O59E	Strong	Autosomal recessive	[3]
Pontocerebellar hypoplasia type 2	DISXV76G	Supportive	Autosomal recessive	[4]

12 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 Sen2 (TSEN2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[10]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[19]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Flucloxacillin	DMNUWST	Approved	Flucloxacillin affects the binding of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[12]

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 tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of tRNA-splicing endonuclease subunit Sen2 (TSEN2).	[17]

References

• [1] tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet. 2008 Sep;40(9):1113-8. doi: 10.1038/ng.204.
• [2] Laser capture microdissection of human pancreatic islets reveals novel eQTLs associated with type 2 diabetes.Mol Metab. 2019 Jun;24:98-107. doi: 10.1016/j.molmet.2019.03.004. Epub 2019 Mar 18.
• [3] 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.
• [4] Pontocerebellar hypoplasia type 2 and TSEN2: review of the literature and two novel mutations. Eur J Med Genet. 2013 Jun;56(6):325-30. doi: 10.1016/j.ejmg.2013.03.009. Epub 2013 Apr 3.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Gene expression profile of colon cancer cell lines treated with SN-38. Chemotherapy. 2010;56(1):17-25. doi: 10.1159/000287353. Epub 2010 Feb 24.
• [12] Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury. Toxicol Sci. 2023 Mar 20;192(1):106-116. doi: 10.1093/toxsci/kfad015.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [15] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.