Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRJY7QD)

• DOT Name: CST complex subunit CTC1 (CTC1)
• Synonyms: Conserved telomere maintenance component 1; HBV DNAPTP1-transactivated protein B
• Gene Name: CTC1
• Related Disease:
  Cerebroretinal microangiopathy with calcifications and cysts 1
  Neoplasm
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Bone marrow failure syndrome
  Brain disease
  Calcinosis
  Childhood myelodysplastic syndrome
  Familial tumoral calcinosis
  Glioma
  Hutchinson-Gilford progeria syndrome
  Lung adenocarcinoma
  Metabolic bone disease
  Myelodysplastic syndrome
  Non-small-cell lung cancer
  Pancytopenia
  Paroxysmal nocturnal haemoglobinuria
  Squamous cell carcinoma
  Telomere syndrome
  Melanoma
  Coats plus syndrome
  Dyskeratosis congenita
• UniProt ID: CTC1_HUMAN
• PDB ID: 5W2L; 6W6W; 7U5C; 8D0B; 8D0K; 8SOJ; 8SOK
• Pfam ID: PF15489
• Sequence:
  MAAGRAQVPSSEQAWLEDAQVFIQKTLCPAVKEPNVQLTPLVIDCVKTVWLSQGRNQGST
  LPLSYSFVSVQDLKTHQRLPCCSHLSWSSSAYQAWAQEAGPNGNPLPREQLLLLGTLTDL
  SADLEQECRNGSLYVRDNTGVLSCELIDLDLSWLGHLFLFPRWSYLPPARWNSSGEGHLE
  LWDAPVPVFPLTISPGPVTPIPVLYPESASCLLRLRNKLRGVQRNLAGSLVRLSALVKSK
  QKAYFILSLGRSHPAVTHVSIIVQVPAQLVWHRALRPGTAYVLTELRVSKIRGQRQHVWM
  TSQSSRLLLLKPECVQELELELEGPLLEADPKPLPMPSNSEDKKDPESLVRYSRLLSYSG
  AVTGVLNEPAGLYELDGQLGLCLAYQQFRGLRRVMRPGVCLQLQDVHLLQSVGGGTRRPV
  LAPCLRGAVLLQSFSRQKPGAHSSRQAYGASLYEQLVWERQLGLPLYLWATKALEELACK
  LCPHVLRHHQFLQHSSPGSPSLGLQLLAPTLDLLAPPGSPVRNAHNEILEEPHHCPLQKY
  TRLQTPSSFPTLATLKEEGQRKAWASFDPKALLPLPEASYLPSCQLNRRLAWSWLCLLPS
  AFCPAQVLLGVLVASSHKGCLQLRDQSGSLPCLLLAKHSQPLSDPRLIGCLVRAERFQLI
  VERDVRSSFPSWKELSMPGFIQKQQARVYVQFFLADALILPVPRPCLHSATPSTPQTDPT
  GPEGPHLGQSRLFLLCHKEALMKRNFCVPPGASPEVPKPALSFYVLGSWLGGTQRKEGTG
  WGLPEPQGNDDNDQKVHLIFFGSSVRWFEFLHPGQVYRLIAPGPATPMLFEKDGSSCISR
  RPLELAGCASCLTVQDNWTLELESSQDIQDVLDANKSLPESSLTDLLSDNFTDSLVSFSA
  EILSRTLCEPLVASLWMKLGNTGAMRRCVKLTVALETAECEFPPHLDVYIEDPHLPPSLG
  LLPGARVHFSQLEKRVSRSHNVYCCFRSSTYVQVLSFPPETTISIPLPHIYLAELLQGGQ
  SPFQATASCHIVSVFSLQLFWVCAYCTSICRQGKCTRLGSTCPTQTAISQAIIRLLVEDG
  TAEAVVTCRNHHVAAALGLCPREWASLLDFVQVPGRVVLQFAGPGAQLESSARVDEPMTM
  FLWTLCTSPSVLRPIVLSFELERKPSKIVPLEPPRLQRFQCGELPFLTHVNPRLRLSCLS
  IRESEYSSSLGILASSC
• Function: Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. Initially the CST complex has been proposed to protect telomeres from DNA degradation. However, the CST complex has been shown to be involved in several aspects of telomere replication. The CST complex inhibits telomerase and is involved in telomere length homeostasis; it is proposed to bind to newly telomerase-synthesized 3' overhangs and to terminate telomerase action implicating the association with the ACD:POT1 complex thus interfering with its telomerase stimulation activity. The CST complex is also proposed to be involved in fill-in synthesis of the telomeric C-strand probably implicating recruitment and activation of DNA polymerase alpha. The CST complex facilitates recovery from many forms of exogenous DNA damage; seems to be involved in the re-initiation of DNA replication at repaired forks and/or dormant origins. Involved in telomere maintenance. Involved in genome stability. May be in involved in telomeric C-strand fill-in during late S/G2 phase.
• Reactome Pathway:
  Telomere C-strand synthesis initiation (R-HSA-174430)
  Polymerase switching on the C-strand of the telomere (R-HSA-174411)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebroretinal microangiopathy with calcifications and cysts 1	DISX0KNA	Definitive	Autosomal recessive	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Bone marrow failure syndrome	DISVUY1J	Strong	Genetic Variation	[4]
Brain disease	DIS6ZC3X	Strong	Biomarker	[5]
Calcinosis	DISQP4OR	Strong	Biomarker	[5]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Genetic Variation	[4]
Familial tumoral calcinosis	DISYJZKG	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Genetic Variation	[6]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Genetic Variation	[7]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[8]
Metabolic bone disease	DISO7RI8	Strong	Biomarker	[5]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Pancytopenia	DISVKEHV	Strong	Genetic Variation	[4]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Genetic Variation	[4]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[8]
Telomere syndrome	DISLXQHV	Strong	Genetic Variation	[10]
Melanoma	DIS1RRCY	moderate	Biomarker	[11]
Coats plus syndrome	DIS11ELA	Supportive	Autosomal recessive	[5]
Dyskeratosis congenita	DISSXV0K	Supportive	Autosomal dominant	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of CST complex subunit CTC1 (CTC1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CST complex subunit CTC1 (CTC1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CST complex subunit CTC1 (CTC1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of CST complex subunit CTC1 (CTC1).	[17]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of CST complex subunit CTC1 (CTC1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of CST complex subunit CTC1 (CTC1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of CST complex subunit CTC1 (CTC1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of CST complex subunit CTC1 (CTC1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CST complex subunit CTC1 (CTC1).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of CST complex subunit CTC1 (CTC1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of CST complex subunit CTC1 (CTC1).	[20]

References

• [1] Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet. 2012 Mar 9;90(3):540-9. doi: 10.1016/j.ajhg.2012.02.002. Epub 2012 Mar 1.
• [2] Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing in ALK-Rearranged Non-Small-Cell Lung Cancer.Clin Cancer Res. 2019 Nov 15;25(22):6671-6682. doi: 10.1158/1078-0432.CCR-19-1176. Epub 2019 Aug 22.
• [3] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [4] Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure.Br J Haematol. 2019 Jun;185(5):935-939. doi: 10.1111/bjh.15862. Epub 2019 Mar 19.
• [5] Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet. 2012 Jan 22;44(3):338-42. doi: 10.1038/ng.1084.
• [6] Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.Oncotarget. 2015 Dec 15;6(40):42468-77. doi: 10.18632/oncotarget.6468.
• [7] CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures.Mol Genet Genomic Med. 2018 Nov;6(6):1148-1156. doi: 10.1002/mgg3.495. Epub 2018 Nov 4.
• [8] Post-Surgery Circulating Tumor Cells and AXL Overexpression as New Poor Prognostic Biomarkers in Resected Lung Adenocarcinoma.Cancers (Basel). 2019 Nov 7;11(11):1750. doi: 10.3390/cancers11111750.
• [9] Association of circulating tumour cells with early relapse and 18F-fluorodeoxyglucose positron emission tomography uptake in resected non-small-cell lung cancers.Eur J Cardiothorac Surg. 2017 Jul 1;52(1):55-62. doi: 10.1093/ejcts/ezx049.
• [10] Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus.Aging Cell. 2013 Dec;12(6):1100-9. doi: 10.1111/acel.12139. Epub 2013 Sep 4.
• [11] CTC1 increases the radioresistance of human melanoma cells by inhibiting telomere shortening and apoptosis.Int J Mol Med. 2014 Jun;33(6):1484-90. doi: 10.3892/ijmm.2014.1721. Epub 2014 Apr 2.
• [12] Dyskeratosis Congenita and Related Telomere Biology Disorders. 2009 Nov 12 [updated 2023 Jan 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] 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.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] 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.
• [18] 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.
• [19] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [20] 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.
• [21] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.