Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB3UCTB)

• DOT Name: Transcription elongation factor SPT4 (SUPT4H1)
• Synonyms: hSPT4; DRB sensitivity-inducing factor 14 kDa subunit; DSIF p14; DRB sensitivity-inducing factor small subunit; DSIF small subunit
• Gene Name: SUPT4H1
• Related Disease:
  Colorectal carcinoma
  Huntington disease
  Spinocerebellar ataxia type 36
  Amyotrophic lateral sclerosis
• UniProt ID: SPT4H_HUMAN
• PDB ID: 3H7H; 5OIK; 6GMH; 6GML; 6TED; 7OKY; 7UND; 7YCX; 8P4C; 8P4D; 8P4F
• Pfam ID: PF06093
• Sequence:
  MALETVPKDLRHLRACLLCSLVKTIDQFEYDGCDNCDAYLQMKGNREMVYDCTSSSFDGI
  IAMMSPEDSWVSKWQRVSNFKPGVYAVSVTGRLPQGIVRELKSRGVAYKSRDTAIKT
• 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: Widely 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)
  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)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Huntington disease	DISQPLA4	Strong	Biomarker	[2]
Spinocerebellar ataxia type 36	DISP7IPL	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Disputed	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transcription elongation factor SPT4 (SUPT4H1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Transcription elongation factor SPT4 (SUPT4H1).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Transcription elongation factor SPT4 (SUPT4H1).	[6]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Transcription elongation factor SPT4 (SUPT4H1).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Transcription elongation factor SPT4 (SUPT4H1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Transcription elongation factor SPT4 (SUPT4H1).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Transcription elongation factor SPT4 (SUPT4H1).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Transcription elongation factor SPT4 (SUPT4H1).	[10]

References

• [1] Transcriptome analysis of paired primary colorectal carcinoma and liver metastases reveals fusion transcripts and similar gene expression profiles in primary carcinoma and liver metastases.BMC Cancer. 2016 Jul 26;16:539. doi: 10.1186/s12885-016-2596-3.
• [2] Effects on murine behavior and lifespan of selectively decreasing expression of mutant huntingtin allele by supt4h knockdown.PLoS Genet. 2015 Mar 11;11(3):e1005043. doi: 10.1371/journal.pgen.1005043. eCollection 2015 Mar.
• [3] Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity.Brain Res. 2019 May 15;1711:29-40. doi: 10.1016/j.brainres.2018.12.045. Epub 2019 Jan 2.
• [4] SUPT4H1 Depletion Leads to a Global Reduction in RNA.Cell Rep. 2019 Jan 2;26(1):45-53.e4. doi: 10.1016/j.celrep.2018.12.004.
• [5] 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.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [8] 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.
• [9] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.