Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCS9LW3)

• DOT Name: Transcription elongation factor SPT5 (SUPT5H)
• Synonyms: hSPT5; DRB sensitivity-inducing factor 160 kDa subunit; DSIF p160; DRB sensitivity-inducing factor large subunit; DSIF large subunit; Tat-cotransactivator 1 protein; Tat-CT1 protein
• Gene Name: SUPT5H
• Related Disease:
  Herpes simplex infection
  Advanced cancer
  Neoplasm
• UniProt ID: SPT5H_HUMAN
• PDB ID: 2DO3; 2E6Z; 2E70; 3H7H; 4L1U; 5OHO; 5OHQ; 5OIK; 5U98; 6EQY; 6ER0; 6GMH; 6GML; 6TED; 7OKX; 7OKY; 7OL0; 7PKS; 7UNC; 7UND; 7YCX; 8P4C; 8P4D; 8P4E; 8P4F
• Pfam ID: PF00467 ; PF03439 ; PF11942
• Sequence:
  MSDSEDSNFSEEEDSERSSDGEEAEVDEERRSAAGSEKEEEPEDEEEEEEEEEYDEEEEE
  EDDDRPPKKPRHGGFILDEADVDDEYEDEDQWEDGAEDILEKEEIEASNIDNVVLDEDRS
  GARRLQNLWRDQREEELGEYYMKKYAKSSVGETVYGGSDELSDDITQQQLLPGVKDPNLW
  TVKCKIGEERATAISLMRKFIAYQFTDTPLQIKSVVAPEHVKGYIYVEAYKQTHVKQAIE
  GVGNLRLGYWNQQMVPIKEMTDVLKVVKEVANLKPKSWVRLKRGIYKDDIAQVDYVEPSQ
  NTISLKMIPRIDYDRIKARMSLKDWFAKRKKFKRPPQRLFDAEKIRSLGGDVASDGDFLI
  FEGNRYSRKGFLFKSFAMSAVITEGVKPTLSELEKFEDQPEGIDLEVVTESTGKEREHNF
  QPGDNVEVCEGELINLQGKILSVDGNKITIMPKHEDLKDMLEFPAQELRKYFKMGDHVKV
  IAGRFEGDTGLIVRVEENFVILFSDLTMHELKVLPRDLQLCSETASGVDVGGQHEWGELV
  QLDPQTVGVIVRLERETFQVLNMYGKVVTVRHQAVTRKKDNRFAVALDSEQNNIHVKDIV
  KVIDGPHSGREGEIRHLFRSFAFLHCKKLVENGGMFVCKTRHLVLAGGSKPRDVTNFTVG
  GFAPMSPRISSPMHPSAGGQRGGFGSPGGGSGGMSRGRGRRDNELIGQTVRISQGPYKGY
  IGVVKDATESTARVELHSTCQTISVDRQRLTTVGSRRPGGMTSTYGRTPMYGSQTPMYGS
  GSRTPMYGSQTPLQDGSRTPHYGSQTPLHDGSRTPAQSGAWDPNNPNTPSRAEEEYEYAF
  DDEPTPSPQAYGGTPNPQTPGYPDPSSPQVNPQYNPQTPGTPAMYNTDQFSPYAAPSPQG
  SYQPSPSPQSYHQVAPSPAGYQNTHSPASYHPTPSPMAYQASPSPSPVGYSPMTPGAPSP
  GGYNPHTPGSGIEQNSSDWVTTDIQVKVRDTYLDTQVVGQTGVIRSVTGGMCSVYLKDSE
  KVVSISSEHLEPITPTKNNKVKVILGEDREATGVLLSIDGEDGIVRMDLDEQLKILNLRF
  LGKLLEA
• Function: Component of the DRB sensitivity-inducing factor complex (DSIF complex), which regulates mRNA processing and transcription elongation by RNA polymerase II. DSIF positively regulates mRNA capping by stimulating the mRNA guanylyltransferase activity of RNGTT/CAP1A. DSIF also acts cooperatively with the negative elongation factor complex (NELF complex) to enhance transcriptional pausing at sites proximal to the promoter. Transcriptional pausing may facilitate the assembly of an elongation competent RNA polymerase II complex. DSIF and NELF promote pausing by inhibition of the transcription elongation factor TFIIS/S-II. TFIIS/S-II binds to RNA polymerase II at transcription pause sites and stimulates the weak intrinsic nuclease activity of the enzyme. Cleavage of blocked transcripts by RNA polymerase II promotes the resumption of transcription from the new 3' terminus and may allow repeated attempts at transcription through natural pause sites. DSIF can also positively regulate transcriptional elongation and is required for the efficient activation of transcriptional elongation by the HIV-1 nuclear transcriptional activator, Tat. DSIF acts to suppress transcriptional pausing in transcripts derived from the HIV-1 LTR and blocks premature release of HIV-1 transcripts at terminator sequences.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  Formation of the Early Elongation Complex (R-HSA-113418)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of the HIV-1 Early Elongation Complex (R-HSA-167158)
  RNA Pol II CTD phosphorylation and interaction with CE during HIV infection (R-HSA-167160)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Abortive elongation of HIV-1 transcript in the absence of Tat (R-HSA-167242)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  mRNA Capping (R-HSA-72086)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  RNA Pol II CTD phosphorylation and interaction with CE (R-HSA-77075)
  Formation of RNA Pol II elongation complex (R-HSA-112382)
• BioCyc Pathway: MetaCyc:G66-31601-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transcription elongation factor SPT5 (SUPT5H).	[3]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcription elongation factor SPT5 (SUPT5H).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Transcription elongation factor SPT5 (SUPT5H).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcription elongation factor SPT5 (SUPT5H).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Transcription elongation factor SPT5 (SUPT5H).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transcription elongation factor SPT5 (SUPT5H).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcription elongation factor SPT5 (SUPT5H).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transcription elongation factor SPT5 (SUPT5H).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcription elongation factor SPT5 (SUPT5H).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Transcription elongation factor SPT5 (SUPT5H).	[6]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Transcription elongation factor SPT5 (SUPT5H).	[11]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Transcription elongation factor SPT5 (SUPT5H).	[12]

References

• [1] CDK9 and SPT5 proteins are specifically required for expression of herpes simplex virus 1 replication-dependent late genes.J Biol Chem. 2017 Sep 15;292(37):15489-15500. doi: 10.1074/jbc.M117.806000. Epub 2017 Jul 25.
• [2] Suppressor of Ty homolog-5, a novel tumor-specific human telomerase reverse transcriptase promoter-binding protein and activator in colon cancer cells.Oncotarget. 2015 Oct 20;6(32):32841-55. doi: 10.18632/oncotarget.5301.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.