Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2YQ9L8)

• DOT Name: Telomere length regulation protein TEL2 homolog (TELO2)
• Synonyms: Protein clk-2 homolog; hCLK2
• Gene Name: TELO2
• Related Disease:
  TELO2-related intellectual disability-neurodevelopmental disorder
  Advanced cancer
  Fanconi anemia complementation group A
  Fanconi's anemia
  Intellectual disability
  leukaemia
  Leukemia
  Nasopharyngeal carcinoma
  Plasma cell myeloma
  Seckel syndrome
  Myocardial ischemia
  Adult lymphoma
  Lymphoma
  Pediatric lymphoma
• UniProt ID: TELO2_HUMAN
• PDB ID: 4PSI; 7F4U; 7OLE
• Pfam ID: PF10193
• Sequence:
  MEPAPSEVRLAVREAIHALSSSEDGGHIFCTLESLKRYLGEMEPPALPREKEEFASAHFS
  PVLRCLASRLSPAWLELLPHGRLEELWASFFLEGPADQAFLVLMETIEGAAGPSFRLMKM
  ARLLARFLREGRLAVLMEAQCRQQTQPGFILLRETLLGKVVALPDHLGNRLQQENLAEFF
  PQNYFRLLGEEVVRVLQAVVDSLQGGLDSSVSFVSQVLGKACVHGRQQEILGVLVPRLAA
  LTQGSYLHQRVCWRLVEQVPDRAMEAVLTGLVEAALGPEVLSRLLGNLVVKNKKAQFVMT
  QKLLFLQSRLTTPMLQSLLGHLAMDSQRRPLLLQVLKELLETWGSSSAIRHTPLPQQRHV
  SKAVLICLAQLGEPELRDSRDELLASMMAGVKCRLDSSLPPVRRLGMIVAEVVSARIHPE
  GPPLKFQYEEDELSLELLALASPQPAGDGASEAGTSLVPATAEPPAETPAEIVDGGVPQA
  QLAGSDSDLDSDDEFVPYDMSGDRELKSSKAPAYVRDCVEALTTSEDIERWEAALRALEG
  LVYRSPTATREVSVELAKVLLHLEEKTCVVGFAGLRQRALVAVTVTDPAPVADYLTSQFY
  ALNYSLRQRMDILDVLTLAAQELSRPGCLGRTPQPGSPSPNTPCLPEAAVSQPGSAVASD
  WRVVVEERIRSKTQRLSKGGPRQGPAGSPSRFNSVAGHFFFPLLQRFDRPLVTFDLLGED
  QLVLGRLAHTLGALMCLAVNTTVAVAMGKALLEFVWALRFHIDAYVRQGLLSAVSSVLLS
  LPAARLLEDLMDELLEARSWLADVAEKDPDEDCRTLALRALLLLQRLKNRLLPPASP
• Function: Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs. Promotes assembly, stabilizes and maintains the activity of mTORC1 and mTORC2 complexes, which regulate cell growth and survival in response to nutrient and hormonal signals. May be involved in telomere length regulation.
• KEGG Pathway:
  Fanconi anemia pathway (hsa03460)
  mTOR sig.ling pathway (hsa04150)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
TELO2-related intellectual disability-neurodevelopmental disorder	DIS9Q6VL	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[3]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[4]
leukaemia	DISS7D1V	Strong	Altered Expression	[5]
Leukemia	DISNAKFL	Strong	Altered Expression	[5]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Altered Expression	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[7]
Seckel syndrome	DISEVUBA	Strong	Genetic Variation	[8]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[9]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[10]
Lymphoma	DISN6V4S	Limited	Biomarker	[10]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[10]

6 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 Telomere length regulation protein TEL2 homolog (TELO2).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Telomere length regulation protein TEL2 homolog (TELO2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Telomere length regulation protein TEL2 homolog (TELO2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Telomere length regulation protein TEL2 homolog (TELO2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Telomere length regulation protein TEL2 homolog (TELO2).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Telomere length regulation protein TEL2 homolog (TELO2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Telomere length regulation protein TEL2 homolog (TELO2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Telomere length regulation protein TEL2 homolog (TELO2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Telomere length regulation protein TEL2 homolog (TELO2).	[14]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Telomere length regulation protein TEL2 homolog (TELO2).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Telomere length regulation protein TEL2 homolog (TELO2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Telomere length regulation protein TEL2 homolog (TELO2).	[18]

References

• [1] 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.
• [2] Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer.Sci Rep. 2017 Dec 5;7(1):17024. doi: 10.1038/s41598-017-17126-2.
• [3] FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex.Mol Cell. 2008 Nov 7;32(3):313-24. doi: 10.1016/j.molcel.2008.10.014.
• [4] A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex. Am J Hum Genet. 2016 May 5;98(5):909-918. doi: 10.1016/j.ajhg.2016.03.014. Epub 2016 Apr 28.
• [5] The ETS factor TEL2 is a hematopoietic oncoprotein.Blood. 2006 Feb 1;107(3):1124-32. doi: 10.1182/blood-2005-03-1196. Epub 2005 Oct 18.
• [6] Snail promotes metastasis of nasopharyngeal carcinoma partly by down-regulating TEL2.Cancer Commun (Lond). 2018 Sep 25;38(1):58. doi: 10.1186/s40880-018-0328-6.
• [7] SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma.Nat Cell Biol. 2013 Jan;15(1):72-81. doi: 10.1038/ncb2651.
• [8] Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome.Mol Genet Genomic Med. 2017 Jul 28;5(5):580-584. doi: 10.1002/mgg3.287. eCollection 2017 Sep.
• [9] The effects of Tel2 on cardiomyocyte survival.Life Sci. 2019 Sep 1;232:116665. doi: 10.1016/j.lfs.2019.116665. Epub 2019 Jul 16.
• [10] The novel ETS factor TEL2 cooperates with Myc in B lymphomagenesis.Mol Cell Biol. 2005 Mar;25(6):2395-405. doi: 10.1128/MCB.25.6.2395-2405.2005.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [14] 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.
• [15] 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.
• [16] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.