Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQLO30U)

• DOT Name: TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L)
• Synonyms: TAF6L; PCAF-associated factor 65-alpha; PAF65-alpha
• Gene Name: TAF6L
• UniProt ID: TAF6L_HUMAN
• PDB ID: 7KTR; 7KTS; 8H7G
• Pfam ID: PF02969 ; PF07571
• Sequence:
  MSEREERRFVEIPRESVRLMAESTGLELSDEVAALLAEDVCYRLREATQNSSQFMKHTKR
  RKLTVEDFNRALRWSSVEAVCGYGSQEALPMRPAREGELYFPEDREVNLVELALATNIPK
  GCAETAVRVHVSYLDGKGNLAPQGSVPSAVSSLTDDLLKYYHQVTRAVLGDDPQLMKVAL
  QDLQTNSKIGALLPYFVYVVSGVKSVSHDLEQLHRLLQVARSLFRNPHLCLGPYVRCLVG
  SVLYCVLEPLAASINPLNDHWTLRDGAALLLSHIFWTHGDLVSGLYQHILLSLQKILADP
  VRPLCCHYGAVVGLHALGWKAVERVLYPHLSTYWTNLQAVLDDYSVSNAQVKADGHKVYG
  AILVAVERLLKMKAQAAEPNRGGPGGRGCRRLDDLPWDSLLFQESSSGGGAEPSFGSGLP
  LPPGGAGPEDPSLSVTLADIYRELYAFFGDSLATRFGTGQPAPTAPRPPGDKKEPAAAPD
  SVRKMPQLTASAIVSPHGDESPRGSGGGGPASASGPAASESRPLPRVHRARGAPRQQGPG
  TGTRDVFQKSRFAPRGAPHFRFIIAGRQAGRRCRGRLFQTAFPAPYGPSPASRYVQKLPM
  IGRTSRPARRWALSDYSLYLPL
• Function: Functions as a component of the PCAF complex. The PCAF complex is capable of efficiently acetylating histones in a nucleosomal context. The PCAF complex could be considered as the human version of the yeast SAGA complex (Probable). With TAF5L, acts as an epigenetic regulator essential for somatic reprogramming. Regulates target genes through H3K9ac deposition and MYC recruitment which trigger MYC regulatory network to orchestrate gene expression programs to control embryonic stem cell state. Functions with MYC to activate target gene expression through RNA polymerase II pause release.
• KEGG Pathway: Basal transcription factors (hsa03022)
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

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 TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[1]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[3]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L (TAF6L).	[9]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [6] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] 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.
• [8] 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.
• [9] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.