Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDF5C72)

• DOT Name: Polycomb group RING finger protein 5 (PCGF5)
• Synonyms: RING finger protein 159
• Gene Name: PCGF5
• Related Disease:
  Mesothelioma
  Barrett esophagus
• UniProt ID: PCGF5_HUMAN
• PDB ID: 4S3O
• Pfam ID: PF16207 ; PF13923
• Sequence:
  MATQRKHLVKDFNPYITCYICKGYLIKPTTVTECLHTFCKTCIVQHFEDSNDCPRCGNQV
  HETNPLEMLRLDNTLEEIIFKLVPGLREQELERESEFWKKNKPQENGQDDTSKADKPKVD
  EEGDENEDDKDYHRSDPQIAICLDCLRNNGQSGDNVVKGLMKKFIRCSTRVTVGTIKKFL
  SLKLKLPSSYELDVLCNGEIMGKDHTMEFIYMTRWRLRGENFRCLNCSASQVCSQDGPLY
  QSYPMVLQYRPRIDFG
• Function: Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity. Plays a redundant role with PCGF3 as part of a PRC1-like complex that mediates monoubiquitination of histone H2A 'Lys-119' on the X chromosome and is required for normal silencing of one copy of the X chromosome in XX females.
• KEGG Pathway:
  Polycomb repressive complex (hsa03083)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mesothelioma	DISKWK9M	Definitive	Biomarker	[1]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[2]

2 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 Polycomb group RING finger protein 5 (PCGF5).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Polycomb group RING finger protein 5 (PCGF5).	[12]

12 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 Polycomb group RING finger protein 5 (PCGF5).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Polycomb group RING finger protein 5 (PCGF5).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Polycomb group RING finger protein 5 (PCGF5).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Polycomb group RING finger protein 5 (PCGF5).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Polycomb group RING finger protein 5 (PCGF5).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Polycomb group RING finger protein 5 (PCGF5).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Polycomb group RING finger protein 5 (PCGF5).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Polycomb group RING finger protein 5 (PCGF5).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polycomb group RING finger protein 5 (PCGF5).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Polycomb group RING finger protein 5 (PCGF5).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Polycomb group RING finger protein 5 (PCGF5).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Polycomb group RING finger protein 5 (PCGF5).	[10]

References

• [1] Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma.Mod Pathol. 2020 Feb;33(2):217-227. doi: 10.1038/s41379-019-0371-0. Epub 2019 Sep 30.
• [2] RING finger proteins are involved in the progression of barrett esophagus to esophageal adenocarcinoma: a preliminary study.Gut Liver. 2014 Sep;8(5):487-94. doi: 10.5009/gnl13133. Epub 2014 Feb 24.
• [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] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [12] 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.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.