Details of Drug Off-Target (DOT)

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

• DOT Name: Telomerase Cajal body protein 1
• Synonyms: WD repeat-containing protein 79; WD40 repeat-containing protein antisense to TP53 gene; WRAP53beta
• Gene Name: WRAP53
• Related Disease:
  Dyskeratosis congenita, autosomal recessive 3
  Dyskeratosis congenita
• UniProt ID: TCAB1_HUMAN
• PDB ID: 7BGB; 7TRC; 7V9A
• Pfam ID: PF00400
• Sequence:
  MKTLETQPLAPDCCPSDQDPAPAHPSPHASPMNKNADSELMPPPPERGDPPRLSPDPVAG
  SAVSQELREGDPVSLSTPLETEFGSPSELSPRIEEQELSENTSLPAEEANGSLSEEEANG
  PELGSGKAMEDTSGEPAAEDEGDTAWNYSFSQLPRFLSGSWSEFSTQPENFLKGCKWAPD
  GSCILTNSADNILRIYNLPPELYHEGEQVEYAEMVPVLRMVEGDTIYDYCWYSLMSSAQP
  DTSYVASSSRENPIHIWDAFTGELRASFRAYNHLDELTAAHSLCFSPDGSQLFCGFNRTV
  RVFSTARPGRDCEVRATFAKKQGQSGIISCIAFSPAQPLYACGSYGRSLGLYAWDDGSPL
  ALLGGHQGGITHLCFHPDGNRFFSGARKDAELLCWDLRQSGYPLWSLGREVTTNQRIYFD
  LDPTGQFLVSGSTSGAVSVWDTDGPGNDGKPEPVLSFLPQKDCTNGVSLHPSLPLLATAS
  GQRVFPEPTESGDEGEELGLPLLSTRHVHLECRLQLWWCGGAPDSSIPDDHQGEKGQGGT
  EGGVGELI
• Function: RNA chaperone that plays a key role in telomere maintenance and RNA localization to Cajal bodies. Specifically recognizes and binds the Cajal body box (CAB box) present in both small Cajal body RNAs (scaRNAs) and telomerase RNA template component (TERC). Essential component of the telomerase holoenzyme complex, a ribonucleoprotein complex essential for the replication of chromosome termini that elongates telomeres in most eukaryotes. In the telomerase holoenzyme complex, required to stimulate the catalytic activity of the complex. Acts by specifically binding the CAB box of the TERC RNA and controlling the folding of the CR4/CR5 region of the TERC RNA, a critical step for telomerase activity. In addition, also controls telomerase holoenzyme complex localization to Cajal body. During S phase, required for delivery of TERC to telomeres during S phase and for telomerase activity. In addition to its role in telomere maintenance, also required for Cajal body formation, probably by mediating localization of scaRNAs to Cajal bodies. Also plays a role in DNA repair: phosphorylated by ATM in response to DNA damage and relocalizes to sites of DNA double-strand breaks to promote the repair of DNA double-strand breaks. Acts by recruiting the ubiquitin ligase RNF8 to DNA breaks and promote both homologous recombination (HR) and non-homologous end joining (NHEJ).
• Tissue Specificity: Expressed in all tissues and cell lines examined.
• Reactome Pathway:
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)
  Telomere Extension By Telomerase (R-HSA-171319)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dyskeratosis congenita, autosomal recessive 3	DISIAV4E	Definitive	Autosomal recessive	[1]
Dyskeratosis congenita	DISSXV0K	Moderate	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Telomerase Cajal body protein 1.	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Telomerase Cajal body protein 1.	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Telomerase Cajal body protein 1.	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Telomerase Cajal body protein 1.	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of Telomerase Cajal body protein 1.	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Telomerase Cajal body protein 1.	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Telomerase Cajal body protein 1.	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Telomerase Cajal body protein 1.	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Telomerase Cajal body protein 1.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Telomerase Cajal body protein 1.	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Telomerase Cajal body protein 1.	[10]

References

• [1] Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 2011 Jan 1;25(1):11-6. doi: 10.1101/gad.2006411.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] 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.
• [4] 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.
• [5] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.
• [10] 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.