Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9XWMQZ)

• DOT Name: FACT complex subunit SPT16 (SUPT16H)
• Synonyms: Chromatin-specific transcription elongation factor 140 kDa subunit; FACT 140 kDa subunit; FACTp140; Facilitates chromatin transcription complex subunit SPT16; hSPT16
• Gene Name: SUPT16H
• Related Disease:
  Autism spectrum disorder
  Intellectual disability
  Megalencephaly
  Mental disorder
  Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum
  Complex neurodevelopmental disorder
• UniProt ID: SP16H_HUMAN
• PDB ID: 4Z2M; 4Z2N; 5E5B; 5UMT; 5UMU; 5XM2; 6UPK; 6UPL; 8I17
• Pfam ID: PF14826 ; PF00557 ; PF08512 ; PF08644 ; PF21091
• Sequence:
  MAVTLDKDAYYRRVKRLYSNWRKGEDEYANVDAIVVSVGVDEEIVYAKSTALQTWLFGYE
  LTDTIMVFCDDKIIFMASKKKVEFLKQIANTKGNENANGAPAITLLIREKNESNKSSFDK
  MIEAIKESKNGKKIGVFSKDKFPGEFMKSWNDCLNKEGFDKIDISAVVAYTIAVKEDGEL
  NLMKKAASITSEVFNKFFKERVMEIVDADEKVRHSKLAESVEKAIEEKKYLAGADPSTVE
  MCYPPIIQSGGNYNLKFSVVSDKNHMHFGAITCAMGIRFKSYCSNLVRTLMVDPSQEVQE
  NYNFLLQLQEELLKELRHGVKICDVYNAVMDVVKKQKPELLNKITKNLGFGMGIEFREGS
  LVINSKNQYKLKKGMVFSINLGFSDLTNKEGKKPEEKTYALFIGDTVLVDEDGPATVLTS
  VKKKVKNVGIFLKNEDEEEEEEEKDEAEDLLGRGSRAALLTERTRNEMTAEEKRRAHQKE
  LAAQLNEEAKRRLTEQKGEQQIQKARKSNVSYKNPSLMPKEPHIREMKIYIDKKYETVIM
  PVFGIATPFHIATIKNISMSVEGDYTYLRINFYCPGSALGRNEGNIFPNPEATFVKEITY
  RASNIKAPGEQTVPALNLQNAFRIIKEVQKRYKTREAEEKEKEGIVKQDSLVINLNRSNP
  KLKDLYIRPNIAQKRMQGSLEAHVNGFRFTSVRGDKVDILYNNIKHALFQPCDGEMIIVL
  HFHLKNAIMFGKKRHTDVQFYTEVGEITTDLGKHQHMHDRDDLYAEQMEREMRHKLKTAF
  KNFIEKVEALTKEELEFEVPFRDLGFNGAPYRSTCLLQPTSSALVNATEWPPFVVTLDEV
  ELIHFERVQFHLKNFDMVIVYKDYSKKVTMINAIPVASLDPIKEWLNSCDLKYTEGVQSL
  NWTKIMKTIVDDPEGFFEQGGWSFLEPEGEGSDAEEGDSESEIEDETFNPSEDDYEEEEE
  DSDEDYSSEAEESDYSKESLGSEEESGKDWDELEEEARKADRESRYEEEEEQSRSMSRKR
  KASVHSSGRGSNRGSRHSSAPPKKKRK
• Function: Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes. The FACT complex is involved in multiple processes that require DNA as a template such as mRNA elongation, DNA replication and DNA repair. During transcription elongation the FACT complex acts as a histone chaperone that both destabilizes and restores nucleosomal structure. It facilitates the passage of RNA polymerase II and transcription by promoting the dissociation of one histone H2A-H2B dimer from the nucleosome, then subsequently promotes the reestablishment of the nucleosome following the passage of RNA polymerase II. The FACT complex is probably also involved in phosphorylation of 'Ser-392' of p53/TP53 via its association with CK2 (casein kinase II).
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  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)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[1]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[1]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[2]
Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum	DISR99J3	Strong	Autosomal dominant	[1]
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of FACT complex subunit SPT16 (SUPT16H).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of FACT complex subunit SPT16 (SUPT16H).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of FACT complex subunit SPT16 (SUPT16H).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of FACT complex subunit SPT16 (SUPT16H).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of FACT complex subunit SPT16 (SUPT16H).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of FACT complex subunit SPT16 (SUPT16H).	[4]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of FACT complex subunit SPT16 (SUPT16H).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of FACT complex subunit SPT16 (SUPT16H).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of FACT complex subunit SPT16 (SUPT16H).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of FACT complex subunit SPT16 (SUPT16H).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of FACT complex subunit SPT16 (SUPT16H).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of FACT complex subunit SPT16 (SUPT16H).	[17]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of FACT complex subunit SPT16 (SUPT16H).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of FACT complex subunit SPT16 (SUPT16H).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of FACT complex subunit SPT16 (SUPT16H).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of FACT complex subunit SPT16 (SUPT16H).	[14]

References

• [1] Novel 14q11.2 microduplication including the CHD8 and SUPT16H genes associated with developmental delay. Am J Med Genet A. 2016 May;170A(5):1325-9. doi: 10.1002/ajmg.a.37579. Epub 2016 Feb 2.
• [2] Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor.Eur J Med Genet. 2016 Sep;59(9):436-43. doi: 10.1016/j.ejmg.2016.08.003. Epub 2016 Aug 9.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] 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.
• [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] 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] 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.
• [8] 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.
• [9] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [10] 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.
• [11] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [12] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] 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.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [18] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.