Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBSAS0V)

• DOT Name: Telomeric repeat-binding factor 2 (TERF2)
• Synonyms: TTAGGG repeat-binding factor 2; Telomeric DNA-binding protein
• Gene Name: TERF2
• UniProt ID: TERF2_HUMAN
• PDB ID: 1H6P; 1VF9; 1VFC; 1W0U; 1XG1; 3BU8; 3BUA; 3K6G; 3SJM; 4M7C; 4RQI; 5WQD; 5XYF; 6J67; 7C5D
• Pfam ID: PF00249 ; PF16772 ; PF08558
• Sequence:
  MAAGAGTAGPASGPGVVRDPAASQPRKRPGREGGEGARRSDTMAGGGGSSDGSGRAAGRR
  ASRSSGRARRGRHEPGLGGPAERGAGEARLEEAVNRWVLKFYFHEALRAFRGSRYGDFRQ
  IRDIMQALLVRPLGKEHTVSRLLRVMQCLSRIEEGENLDCSFDMEAELTPLESAINVLEM
  IKTEFTLTEAVVESSRKLVKEAAVIICIKNKEFEKASKILKKHMSKDPTTQKLRNDLLNI
  IREKNLAHPVIQNFSYETFQQKMLRFLESHLDDAEPYLLTMAKKALKSESAASSTGKEDK
  QPAPGPVEKPPREPARQLRNPPTTIGMMTLKAAFKTLSGAQDSEAAFAKLDQKDLVLPTQ
  ALPASPALKNKRPRKDENESSAPADGEGGSELQPKNKRMTISRLVLEEDSQSTEPSAGLN
  SSQEAASAPPSKPTVLNQPLPGEKNPKVPKGKWNSSNGVEEKETWVEEDELFQVQAAPDE
  DSTTNITKKQKWTVEESEWVKAGVQKYGEGNWAAISKNYPFVNRTAVMIKDRWRTMKRLG
  MN
• Function: Binds the telomeric double-stranded 5'-TTAGGG-3' repeat and plays a central role in telomere maintenance and protection against end-to-end fusion of chromosomes. In addition to its telomeric DNA-binding role, required to recruit a number of factors and enzymes required for telomere protection, including the shelterin complex, TERF2IP/RAP1 and DCLRE1B/Apollo. 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. Together with DCLRE1B/Apollo, plays a key role in telomeric loop (T loop) formation by generating 3' single-stranded overhang at the leading end telomeres: T loops have been proposed to protect chromosome ends from degradation and repair. Required both to recruit DCLRE1B/Apollo to telomeres and activate the exonuclease activity of DCLRE1B/Apollo. Preferentially binds to positive supercoiled DNA. Together with DCLRE1B/Apollo, required to control the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Recruits TERF2IP/RAP1 to telomeres, thereby participating in to repressing homology-directed repair (HDR), which can affect telomere length.
• Tissue Specificity: Ubiquitous. Highly expressed in spleen, thymus, prostate, uterus, testis, small intestine, colon and peripheral blood leukocytes.
• 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 decreases the expression of Telomeric repeat-binding factor 2 (TERF2).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Telomeric repeat-binding factor 2 (TERF2).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Telomeric repeat-binding factor 2 (TERF2).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Telomeric repeat-binding factor 2 (TERF2).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Telomeric repeat-binding factor 2 (TERF2).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Telomeric repeat-binding factor 2 (TERF2).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Telomeric repeat-binding factor 2 (TERF2).	[7]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Telomeric repeat-binding factor 2 (TERF2).	[8]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Telomeric repeat-binding factor 2 (TERF2).	[9]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Telomeric repeat-binding factor 2 (TERF2).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Telomeric repeat-binding factor 2 (TERF2).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Telomeric repeat-binding factor 2 (TERF2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Telomeric repeat-binding factor 2 (TERF2).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals. Environ Res. 2015 Jan;136:462-9. doi: 10.1016/j.envres.2014.09.040. Epub 2014 Nov 25.
• [6] 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.
• [7] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [8] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [9] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [10] Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells. Environ Sci Pollut Res Int. 2016 Feb;23(3):2173-85. doi: 10.1007/s11356-015-5187-y. Epub 2015 Sep 2.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.