Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1JMX8U)

• DOT Name: Polyhomeotic-like protein 1 (PHC1)
• Synonyms: hPH1; Early development regulatory protein 1
• Gene Name: PHC1
• Related Disease:
  Bjornstad syndrome
  Glioma
  Abdominal aortic aneurysm
  Acute lymphocytic leukaemia
  Allergic asthma
  Childhood acute lymphoblastic leukemia
  Clear cell renal carcinoma
  Embryonal neoplasm
  Germ cell tumor
  leukaemia
  Leukemia
  Tetralogy of fallot
  Autosomal recessive primary microcephaly
  Arthritis
  Congenital heart disease
  Microcephaly 11, primary, autosomal recessive
  Thalassemia
• UniProt ID: PHC1_HUMAN
• PDB ID: 2L8E
• Pfam ID: PF16616 ; PF00536 ; PF21319
• Sequence:
  METESEQNSNSTNGSSSSGGSSRPQIAQMSLYERQAVQALQALQRQPNAAQYFHQFMLQQ
  QLSNAQLHSLAAVQQATIAASRQASSPNTSTTQQQTTTTQASINLATTSAAQLISRSQSV
  SSPSATTLTQSVLLGNTTSPPLNQSQAQMYLRPQLGNLLQVNRTLGRNVPLASQLILMPN
  GAVAAVQQEVPSAQSPGVHADADQVQNLAVRNQQASAQGPQMQGSTQKAIPPGASPVSSL
  SQASSQALAVAQASSGATNQSLNLSQAGGGSGNSIPGSMGPGGGGQAHGGLGQLPSSGMG
  GGSCPRKGTGVVQPLPAAQTVTVSQGSQTEAESAAAKKAEADGSGQQNVGMNLTRTATPA
  PSQTLISSATYTQIQPHSLIQQQQQIHLQQKQVVIQQQIAIHHQQQFQHRQSQLLHTATH
  LQLAQQQQQQQQQQQQQQQPQATTLTAPQPPQVPPTQQVPPSQSQQQAQTLVVQPMLQSS
  PLSLPPDAAPKPPIPIQSKPPVAPIKPPQLGAAKMSAAQQPPPHIPVQVVGTRQPGTAQA
  QALGLAQLAAAVPTSRGMPGTVQSGQAHLASSPPSSQAPGALQECPPTLAPGMTLAPVQG
  TAHVVKGGATTSSPVVAQVPAAFYMQSVHLPGKPQTLAVKRKADSEEERDDVSTLGSMLP
  AKASPVAESPKVMDEKSSLGEKAESVANVNANTPSSELVALTPAPSVPPPTLAMVSRQMG
  DSKPPQAIVKPQILTHIIEGFVIQEGAEPFPVGCSQLLKESEKPLQTGLPTGLTENQSGG
  PLGVDSPSAELDKKANLLKCEYCGKYAPAEQFRGSKRFCSMTCAKRYNVSCSHQFRLKRK
  KMKEFQEANYARVRRRGPRRSSSDIARAKIQGKCHRGQEDSSRGSDNSSYDEALSPTSPG
  PLSVRAGHGERDLGNPNTAPPTPELHGINPVFLSSNPSRWSVEEVYEFIASLQGCQEIAE
  EFRSQEIDGQALLLLKEEHLMSAMNIKLGPALKICAKINVLKET
• 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. Required for proper control of cellular levels of GMNN expression.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA methylation proteins (R-HSA-4655427)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bjornstad syndrome	DISO267N	Definitive	Biomarker	[1]
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[3]
Allergic asthma	DISHF0H3	Strong	Biomarker	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[5]
Embryonal neoplasm	DIS5MQSB	Strong	Biomarker	[6]
Germ cell tumor	DIS62070	Strong	Biomarker	[6]
leukaemia	DISS7D1V	Strong	Altered Expression	[3]
Leukemia	DISNAKFL	Strong	Altered Expression	[3]
Tetralogy of fallot	DISMHFNW	Strong	Biomarker	[7]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[8]
Arthritis	DIST1YEL	Limited	Biomarker	[9]
Congenital heart disease	DISQBA23	Limited	Biomarker	[10]
Microcephaly 11, primary, autosomal recessive	DIS07CMQ	Limited	Autosomal recessive	[11]
Thalassemia	DIS76XZB	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Polyhomeotic-like protein 1 (PHC1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Polyhomeotic-like protein 1 (PHC1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Polyhomeotic-like protein 1 (PHC1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Polyhomeotic-like protein 1 (PHC1).	[16]
Marinol	DM70IK5	Approved	Marinol increases the expression of Polyhomeotic-like protein 1 (PHC1).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Polyhomeotic-like protein 1 (PHC1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polyhomeotic-like protein 1 (PHC1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Polyhomeotic-like protein 1 (PHC1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Polyhomeotic-like protein 1 (PHC1).	[21]

References

• [1] Enhanced delivery efficiency of recombinant adenovirus into tumor and mesenchymal stem cells by a novel PTD.Cancer Gene Ther. 2008 Nov;15(11):703-12. doi: 10.1038/cgt.2008.45. Epub 2008 Jul 4.
• [2] NOX isoforms in the development of abdominal aortic aneurysm.Redox Biol. 2017 Apr;11:118-125. doi: 10.1016/j.redox.2016.11.002. Epub 2016 Nov 19.
• [3] Lack of the Polycomb-group gene rae28 causes maturation arrest at the early B-cell developmental stage.Exp Hematol. 2001 Jan;29(1):93-103. doi: 10.1016/s0301-472x(00)00620-2.
• [4] Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation.Nat Med. 2006 May;12(5):574-9. doi: 10.1038/nm1385. Epub 2006 Apr 9.
• [5] Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays.Mod Pathol. 2006 May;19(5):684-94. doi: 10.1038/modpathol.3800577.
• [6] Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity. Biochim Biophys Acta. 2005 Oct 15;1731(1):48-56. doi: 10.1016/j.bbaexp.2005.08.006. Epub 2005 Sep 1.
• [7] Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells.J Exp Med. 2002 Mar 18;195(6):759-70. doi: 10.1084/jem.20011911.
• [8] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [9] Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis.Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19875-80. doi: 10.1073/pnas.0805198105. Epub 2008 Dec 9.
• [10] The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis.J Clin Invest. 2002 Jul;110(2):177-84. doi: 10.1172/JCI14839.
• [11] Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Hum Mol Genet. 2013 Jun 1;22(11):2200-13. doi: 10.1093/hmg/ddt072. Epub 2013 Feb 14.
• [12] Beta thalassemic mutations recognized by DNA mapping with Hph I and Rsa I in the Algerian population.Biochem Biophys Res Commun. 1983 May 31;113(1):269-72. doi: 10.1016/0006-291x(83)90461-8.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity. Biochim Biophys Acta. 2005 Oct 15;1731(1):48-56. doi: 10.1016/j.bbaexp.2005.08.006. Epub 2005 Sep 1.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.