Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT861N2N)

• DOT Name: TERF1-interacting nuclear factor 2 (TINF2)
• Synonyms: TRF1-interacting nuclear protein 2
• Gene Name: TINF2
• Related Disease:
  Bone marrow failure syndrome
  Cerebellar disorder
  Dyskeratosis congenita, X-linked
  Nail disorder
  Revesz syndrome
  Acute leukaemia
  Adult lymphoma
  Adult T-cell leukemia/lymphoma
  Aplastic anemia
  Bone osteosarcoma
  Breast neoplasm
  Cerebellar ataxia
  Coats plus syndrome
  Dyskeratosis congenita, autosomal dominant 3
  Gastric cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  Lymphoma
  Osteosarcoma
  Pediatric lymphoma
  Plasma cell myeloma
  Pulmonary disease
  Stomach cancer
  T-cell leukaemia
  Telomere syndrome
  Advanced cancer
  Pulmonary fibrosis
  Dyskeratosis congenita
  Hoyeraal-Hreidarsson syndrome
  Small lymphocytic lymphoma
  Thyroid gland papillary carcinoma
• UniProt ID: TINF2_HUMAN
• PDB ID: 3BQO; 3BU8; 5XYF
• Pfam ID: PF14973
• Sequence:
  MATPLVAGPAALRFAAAASWQVVRGRCVEHFPRVLEFLRSLRAVAPGLVRYRHHERLCMG
  LKAKVVVELILQGRPWAQVLKALNHHFPESGPIVRDPKATKQDLRKILEAQETFYQQVKQ
  LSEAPVDLASKLQELEQEYGEPFLAAMEKLLFEYLCQLEKALPTPQAQQLQDVLSWMQPG
  VSITSSLAWRQYGVDMGWLLPECSVTDSVNLAEPMEQNPPQQQRLALHNPLPKAKPGTHL
  PQGPSSRTHPEPLAGRHFNLAPLGRRRVQSQWASTRGGHKERPTVMLFPFRNLGSPTQVI
  SKPESKEEHAIYTADLAMGTRAASTGKSKSPCQTLGGRALKENPVDLPATEQKENCLDCY
  MDPLRLSLLPPRARKPVCPPSLCSSVITIGDLVLDSDEEENGQGEGKESLENYQKTKFDT
  LIPTLCEYLPPSGHGAIPVSSCDCRDSSRPL
• Function: Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG 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. Plays a role in shelterin complex assembly. Isoform 1 may have additional role in tethering telomeres to the nuclear matrix.
• Tissue Specificity: Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• 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

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone marrow failure syndrome	DISVUY1J	Definitive	Genetic Variation	[1]
Cerebellar disorder	DIS2O7WM	Definitive	Biomarker	[2]
Dyskeratosis congenita, X-linked	DISJ3Y69	Definitive	Biomarker	[2]
Nail disorder	DISE7ZR0	Definitive	Biomarker	[2]
Revesz syndrome	DISPIS3W	Definitive	Autosomal dominant	[2]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[3]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[4]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[5]
Aplastic anemia	DISJRSC0	Strong	Genetic Variation	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[8]
Coats plus syndrome	DIS11ELA	Strong	Genetic Variation	[9]
Dyskeratosis congenita, autosomal dominant 3	DISU5O85	Strong	Autosomal dominant	[10]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[11]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Lymphoma	DISN6V4S	Strong	Biomarker	[4]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[13]
Pulmonary disease	DIS6060I	Strong	Biomarker	[14]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[11]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[5]
Telomere syndrome	DISLXQHV	Strong	Biomarker	[15]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[16]
Pulmonary fibrosis	DISQKVLA	Moderate	Autosomal dominant	[10]
Dyskeratosis congenita	DISSXV0K	Supportive	Autosomal dominant	[17]
Hoyeraal-Hreidarsson syndrome	DISAUR8F	Supportive	Autosomal dominant	[18]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[19]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Autosomal dominant	[10]

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 TERF1-interacting nuclear factor 2 (TINF2).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[23]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of TERF1-interacting nuclear factor 2 (TINF2).	[24]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[26]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[27]
Pyrrolidine dithiocarbamate	DM5ZAS6	Investigative	Pyrrolidine dithiocarbamate decreases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[28]
BAY11-7082	DMQNOFA	Investigative	BAY11-7082 decreases the expression of TERF1-interacting nuclear factor 2 (TINF2).	[28]

References

• [1] TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes.Blood. 2008 Nov 1;112(9):3594-600. doi: 10.1182/blood-2008-05-153445. Epub 2008 Jul 30.
• [2] TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet. 2008 Feb;82(2):501-9. doi: 10.1016/j.ajhg.2007.10.004. Epub 2008 Jan 31.
• [3] Decreased gene expression for telomeric-repeat binding factors and TIN2 in malignant hematopoietic cells.Anticancer Res. 2002 Mar-Apr;22(2B):1315-20.
• [4] Gene dosage reductions of Trf1 and/or Tin2 induce telomere DNA damage and lymphoma formation in aging mice.Leukemia. 2017 Dec;31(12):2853. doi: 10.1038/leu.2017.224. Epub 2017 Nov 10.
• [5] Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia.Int J Cancer. 2006 Nov 1;119(9):2090-7. doi: 10.1002/ijc.22026.
• [6] Telomere stability genes are not mutated in osteosarcoma cell lines.Cancer Genet Cytogenet. 2005 Jul 1;160(1):79-81. doi: 10.1016/j.cancergencyto.2004.12.004.
• [7] Coordinate regulation between expression levels of telomere-binding proteins and telomere length in breast carcinomas.Cancer Med. 2012 Oct;1(2):165-75. doi: 10.1002/cam4.14. Epub 2012 Jul 24.
• [8] Ataxia and pancytopenia caused by a mutation in TINF2.Hum Genet. 2008 Dec;124(5):507-13. doi: 10.1007/s00439-008-0576-7. Epub 2008 Nov 1.
• [9] 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.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] Down-regulation of TRF1, TRF2 and TIN2 genes is important to maintain telomeric DNA for gastric cancers.Anticancer Res. 2002 Nov-Dec;22(6A):3303-7.
• [12] Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis.Am J Pathol. 2005 Jan;166(1):73-80. doi: 10.1016/S0002-9440(10)62233-X.
• [13] Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression.Blood Cells Mol Dis. 2014 Feb-Mar;52(2-3):134-9. doi: 10.1016/j.bcmd.2013.10.002. Epub 2013 Nov 14.
• [14] Treatment of dyskeratosis congenita-associated pulmonary fibrosis with danazol.Pediatr Pulmonol. 2015 Dec;50(12):E48-51. doi: 10.1002/ppul.23235. Epub 2015 Jun 17.
• [15] TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity.Mol Cell Biol. 2019 Oct 11;39(21):e00593-18. doi: 10.1128/MCB.00593-18. Print 2019 Nov 1.
• [16] Effects of TIN2 on telomeres and chromosomes in the human gastric epithelial cell line GES-1.Oncol Lett. 2018 Apr;15(4):5161-5166. doi: 10.3892/ol.2018.7927. Epub 2018 Feb 2.
• [17] 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.
• [18] Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita. J Allergy Clin Immunol. 2012 Feb;129(2):473-82, 482.e1-3. doi: 10.1016/j.jaci.2011.09.043. Epub 2011 Nov 10.
• [19] A novel spliced variant of the TIN2 shelterin is present in chronic lymphocytic leukemia.Leuk Res. 2017 Aug;59:66-74. doi: 10.1016/j.leukres.2017.05.017. Epub 2017 May 29.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] 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.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] 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.
• [24] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [25] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [26] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [27] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [28] Transcriptional activation of TINF2, a gene encoding the telomere-associated protein TIN2, by Sp1 and NF-B factors. PLoS One. 2011;6(6):e21333. doi: 10.1371/journal.pone.0021333. Epub 2011 Jun 23.