Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQK3FI4)

• DOT Name: Chromosome transmission fidelity protein 18 homolog (CHTF18)
• Synonyms: hCTF18; CHL12
• Gene Name: CHTF18
• Related Disease:
  Neoplasm
  Advanced cancer
  Colon cancer
  Colon carcinoma
• UniProt ID: CTF18_HUMAN
• Pfam ID: PF00004
• Sequence:
  MEDYEQELCGVEDDFHNQFAAELEVLAELEGASTPSPSGVPLFTAGRPPRTFEEALARGD
  AASSPAPAASVGSSQGGARKRQVDADLQPAGSLPHAPRIKRPRLQVVKRLNFRSEEMEEP
  PPPDSSPTDITPPPSPEDLAELWGHGVSEAAADVGLTRASPAARNPVLRRPPILEDYVHV
  TSTEGVRAYLVLRADPMAPGVQGSLLHVPWRGGGQLDLLGVSLASLKKQVDGERRERLLQ
  EAQKLSDTLHSLRSGEEEAAQPLGAPEEEPTDGQDASSHCLWVDEFAPRHYTELLSDDFT
  NRCLLKWLKLWDLVVFGHERPSRKPRPSVEPARVSKEATAPGKWKSHEQVLEEMLEAGLD
  PSQRPKQKVALLCGPPGLGKTTLAHVIARHAGYSVVEMNASDDRSPEVFRTRIEAATQME
  SVLGAGGKPNCLVIDEIDGAPVAAINVLLSILNRKGPQEVGPQGPAVPSGGGRRRRAEGG
  LLMRPIICICNDQFAPSLRQLKQQAFLLHFPPTLPSRLVQRLQEVSLRQGMRADPGVLAA
  LCEKTDNDIRACINTLQFLYSRGQRELSVRDVQATRVGLKDQRRGLFSVWQEVFQLPRAQ
  RRRVGQDPALPADTLLLGDGDAGSLTSASQRFYRVLHAAASAGEHEKVVQGLFDNFLRLR
  LRDSSLGAVCVALDWLAFDDLLAGAAHHSQSFQLLRYPPFLPVAFHVLFASSHTPRITFP
  SSQQEAQNRMSQMRNLIQTLVSGIAPATRSRATPQALLLDALCLLLDILAPKLRPVSTQL
  YSTREKQQLASLVGTMLAYSLTYRQERTPDGQYIYRLEPNVEELCRFPELPARKPLTYQT
  KQLIAREIEVEKMRRAEASARVENSPQVDGSPPGLEGLLGGIGEKGVHRPAPRNHEQRLE
  HIMRRAAREEQPEKDFFGRVVVRSTAVPSAGDTAPEQDSVERRMGTAVGRSEVWFRFNEG
  VSNAVRRSLYIRDLL
• Function: Chromosome cohesion factor involved in sister chromatid cohesion and fidelity of chromosome transmission. Component of one of the cell nuclear antigen loader complexes, CTF18-replication factor C (CTF18-RFC), which consists of CTF18, CTF8, DCC1, RFC2, RFC3, RFC4 and RFC5. The CTF18-RFC complex binds to single-stranded and primed DNAs and has weak ATPase activity that is stimulated by the presence of primed DNA, replication protein A (RPA) and by proliferating cell nuclear antigen (PCNA). The CTF18-RFC complex catalyzes the ATP-dependent loading of PCNA onto primed and gapped DNA. Interacts with and stimulates DNA polymerase POLH. During DNA repair synthesis, involved in loading DNA polymerase POLE at the sites of local damage.
• Reactome Pathway: Polymerase switching on the C-strand of the telomere (R-HSA-174411)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]

3 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 Chromosome transmission fidelity protein 18 homolog (CHTF18).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the sumoylation of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[16]

11 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 Chromosome transmission fidelity protein 18 homolog (CHTF18).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[13]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Chromosome transmission fidelity protein 18 homolog (CHTF18).	[15]

References

• [1] Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A.PLoS One. 2013 Jun 3;8(6):e63313. doi: 10.1371/journal.pone.0063313. Print 2014.
• [2] CB-6644 Is a Selective Inhibitor of the RUVBL1/2 Complex with Anticancer Activity.ACS Chem Biol. 2019 Feb 15;14(2):236-244. doi: 10.1021/acschembio.8b00904. Epub 2019 Jan 25.
• [3] DNA Replication and Sister Chromatid Cohesion 1 (DSCC1) of the Replication Factor Complex CTF18-RFC is Critical for Colon Cancer Cell Growth.J Cancer. 2019 Oct 15;10(24):6142-6153. doi: 10.7150/jca.32339. eCollection 2019.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability. Cell Cycle. 2017 Apr 18;16(8):802-811. doi: 10.1080/15384101.2017.1302628. Epub 2017 Mar 20.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [15] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [16] 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.