Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMMNZ65)

• DOT Name: Chromatin target of PRMT1 protein (CHTOP)
• Synonyms: Friend of PRMT1 protein; Small arginine- and glycine-rich protein; SRAG
• Gene Name: CHTOP
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Ciliopathy
  Colorectal carcinoma
  Myeloproliferative neoplasm
  Fibrodysplasia ossificans progressiva
• UniProt ID: CHTOP_HUMAN
• Pfam ID: PF13865
• Sequence:
  MAAQSAPKVVLKSTTKMSLNERFTNMLKNKQPTPVNIRASMQQQQQLASARNRRLAQQME
  NRPSVQAALKLKQSLKQRLGKSNIQARLGRPIGALARGAIGGRGLPIIQRGLPRGGLRGG
  RATRTLLRGGMSLRGQNLLRGGRAVAPRMGLRRGGVRGRGGPGRGGLGRGAMGRGGIGGR
  GRGMIGRGRGGFGGRGRGRGRGRGALARPVLTKEQLDNQLDAYMSKTKGHLDAELDAYMA
  QTDPETND
• Function: Plays an important role in the ligand-dependent activation of estrogen receptor target genes. May play a role in the silencing of fetal globin genes. Recruits the 5FMC complex to ZNF148, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes. Plays an important role in the tumorigenicity of glioblastoma cells. Binds to 5-hydroxymethylcytosine (5hmC) and associates with the methylosome complex containing PRMT1, PRMT5, MEP50 and ERH. The CHTOP-methylosome complex associated with 5hmC is recruited to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of genes involved in glioblastomagenesis ; Required for effective mRNA nuclear export and is a component of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. Stimulates DDX39B ATPase and helicase activities. In cooperation with ALYREF/THOC4 enhances NXF1 RNA binding activity.
• Tissue Specificity: Expressed in an erythroid progenitor cell line derived from peripheral blood. Expressed in glioblastoma cells .
• Reactome Pathway:
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[3]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[3]
Ciliopathy	DIS10G4I	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Genetic Variation	[5]
Fibrodysplasia ossificans progressiva	DISAT6WU	moderate	Biomarker	[6]

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 Chromatin target of PRMT1 protein (CHTOP).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Chromatin target of PRMT1 protein (CHTOP).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chromatin target of PRMT1 protein (CHTOP).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Chromatin target of PRMT1 protein (CHTOP).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Chromatin target of PRMT1 protein (CHTOP).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Chromatin target of PRMT1 protein (CHTOP).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Chromatin target of PRMT1 protein (CHTOP).	[13]

1 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 affects the methylation of Chromatin target of PRMT1 protein (CHTOP).	[12]

References

• [1] 5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex.Cell Rep. 2014 Oct 9;9(1):48-60. doi: 10.1016/j.celrep.2014.08.071. Epub 2014 Oct 2.
• [2] New insights into frequency and contents of fear of cancer progression/recurrence (FOP/FCR) in outpatients with colorectal carcinoma (CRC) receiving oral capecitabine: a pilot study at a comprehensive cancer center.Patient Prefer Adherence. 2017 Nov 14;11:1907-1914. doi: 10.2147/PPA.S142784. eCollection 2017.
• [3] SOX17 restrains proliferation and tumor formation by down-regulating activity of the Wnt/-catenin signaling pathway via trans-suppressing -catenin in cervical cancer.Cell Death Dis. 2018 Jul 3;9(7):741. doi: 10.1038/s41419-018-0782-8.
• [4] CEP19 cooperates with FOP and CEP350 to drive early steps in the ciliogenesis programme.Open Biol. 2017 Jun;7(6):170114. doi: 10.1098/rsob.170114.
• [5] FOP is a centriolar satellite protein involved in ciliogenesis.PLoS One. 2013;8(3):e58589. doi: 10.1371/journal.pone.0058589. Epub 2013 Mar 12.
• [6] Animal models of fibrodysplasia ossificans progressiva.Dev Dyn. 2018 Feb;247(2):279-288. doi: 10.1002/dvdy.24606. Epub 2017 Dec 1.
• [7] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] 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.