Details of Drug Off-Target (DOT)

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

• DOT Name: Telomeric repeat-binding factor 1 (TERF1)
• Synonyms: NIMA-interacting protein 2; TTAGGG repeat-binding factor 1; Telomeric protein Pin2/TRF1
• Gene Name: TERF1
• UniProt ID: TERF1_HUMAN
• PDB ID: 1BA5; 1H6O; 1ITY; 1IV6; 1W0T; 3BQO; 3L82; 5HKP; 5WIR; 5XUP; 8F0A; 8F0U; 8F1T; 8F1U; 8F21; 8F26; 8OX1
• Pfam ID: PF00249 ; PF08558
• Sequence:
  MAEDVSSAAPSPRGCADGRDADPTEEQMAETERNDEEQFECQELLECQVQVGAPEEEEEE
  EEDAGLVAEAEAVAAGWMLDFLCLSLCRAFRDGRSEDFRRTRNSAEAIIHGLSSLTACQL
  RTIYICQFLTRIAAGKTLDAQFENDERITPLESALMIWGSIEKEHDKLHEEIQNLIKIQA
  IAVCMENGNFKEAEEVFERIFGDPNSHMPFKSKLLMIISQKDTFHSFFQHFSYNHMMEKI
  KSYVNYVLSEKSSTFLMKAAAKVVESKRTRTITSQDKPSGNDVEMETEANLDTRKSVSDK
  QSAVTESSEGTVSLLRSHKNLFLSKLQHGTQQQDLNKKERRVGTPQSTKKKKESRRATES
  RIPVSKSQPVTPEKHRARKRQAWLWEEDKNLRSGVRKYGEGNWSKILLHYKFNNRTSVML
  KDRWRTMKKLKLISSDSED
• Function: Binds the telomeric double-stranded 5'-TTAGGG-3' repeat and negatively regulates telomere length. Involved in the regulation of the mitotic spindle. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded 5'-TTAGGG-3' repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways.
• Tissue Specificity: Highly expressed and ubiquitous. Isoform Pin2 predominates.
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  Recognition and association of DNA glycosylase with site containing an affected purine (R-HSA-110330)
  Cleavage of the damaged purine (R-HSA-110331)
  Meiotic synapsis (R-HSA-1221632)
  Packaging Of Telomere Ends (R-HSA-171306)
  Telomere Extension By Telomerase (R-HSA-171319)
  Polymerase switching on the C-strand of the telomere (R-HSA-174411)
  Processive synthesis on the C-strand of the telomere (R-HSA-174414)
  Telomere C-strand (Lagging Strand) Synthesis (R-HSA-174417)
  Telomere C-strand synthesis initiation (R-HSA-174430)
  Removal of the Flap Intermediate from the C-strand (R-HSA-174437)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  Inhibition of DNA recombination at telomere (R-HSA-9670095)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

12 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 Telomeric repeat-binding factor 1 (TERF1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Telomeric repeat-binding factor 1 (TERF1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Telomeric repeat-binding factor 1 (TERF1).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Telomeric repeat-binding factor 1 (TERF1).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Telomeric repeat-binding factor 1 (TERF1).	[5]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Telomeric repeat-binding factor 1 (TERF1).	[6]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Telomeric repeat-binding factor 1 (TERF1).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Telomeric repeat-binding factor 1 (TERF1).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Telomeric repeat-binding factor 1 (TERF1).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Telomeric repeat-binding factor 1 (TERF1).	[11]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Telomeric repeat-binding factor 1 (TERF1).	[12]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Telomeric repeat-binding factor 1 (TERF1).	[13]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the localization of Telomeric repeat-binding factor 1 (TERF1).	[8]

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 Telomeric repeat-binding factor 1 (TERF1).	[10]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Up-regulation of telomere-binding TRF1, TRF2 related to reactive oxygen species induced by As(2)O(3) in MGC-803 cells. Eur J Pharmacol. 2005 May 23;516(1):1-9. doi: 10.1016/j.ejphar.2005.04.022.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] NFATc4 mediates ethanol-triggered hepatocyte senescence. Toxicol Lett. 2021 Oct 10;350:10-21. doi: 10.1016/j.toxlet.2021.06.018. Epub 2021 Jun 27.
• [8] Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1. Mech Ageing Dev. 2009 Aug;130(8):528-37. doi: 10.1016/j.mad.2009.06.005. Epub 2009 Jun 25.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [13] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.