Details of Drug Off-Target (DOT)

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

DOT Name	Protection of telomeres protein 1 (POT1)
Synonyms	hPot1; POT1-like telomere end-binding protein
Gene Name	POT1
Related Disease	Acute myelogenous leukaemia ( ) Adult T-cell leukemia/lymphoma ( ) Angiosarcoma ( ) Arteriosclerosis ( ) Atherosclerosis ( ) B-cell neoplasm ( ) Bone osteosarcoma ( ) Breast cancer ( ) Breast carcinoma ( ) Classic Hodgkin lymphoma ( ) Colorectal carcinoma ( ) Endometrial cancer ( ) Endometrial carcinoma ( ) Familial atypical multiple mole melanoma syndrome ( ) Gastric cancer ( ) Glioma ( ) Hepatocellular carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Lymphoid leukemia ( ) Malignant soft tissue neoplasm ( ) Metastatic malignant neoplasm ( ) Osteosarcoma ( ) Plasma cell myeloma ( ) Primary cutaneous T-cell lymphoma ( ) Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8 ( ) Renal cell carcinoma ( ) Rheumatoid arthritis ( ) Sarcoma ( ) Skin cancer ( ) Small lymphocytic lymphoma ( ) Stomach cancer ( ) T-cell leukaemia ( ) Skin neoplasm ( ) Squamous cell carcinoma ( ) Tumor predisposition syndrome 3 ( ) Advanced cancer ( ) Breast neoplasm ( ) Cerebroretinal microangiopathy with calcifications and cysts 3 ( ) Chromosomal disorder ( ) Mesothelioma ( ) Methicillin-resistant staphylococci infection ( ) Obsolete glioma susceptibility 9 ( ) Thyroid cancer ( ) Thyroid gland carcinoma ( ) Thyroid tumor ( )
UniProt ID	POTE1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1XJV; 3KJO; 3KJP; 5H65; 5UN7; 7QXB; 7QXS; 7S1O; 7S1T; 7S1U; 8SH0; 8SH1; 8SOJ; 8SOK
Pfam ID	PF02765 ; PF21375 ; PF16686
Sequence	MSLVPATNYIYTPLNQLKGGTIVNVYGVVKFFKPPYLSKGTDYCSVVTIVDQTNVKLTCL LFSGNYEALPIIYKNGDIVRFHRLKIQVYKKETQGITSSGFASLTFEGTLGAPIIPRTSS KYFNFTTEDHKMVEALRVWASTHMSPSWTLLKLCDVQPMQYFDLTCQLLGKAEVDGASFL LKVWDGTRTPFPSWRVLIQDLVLEGDLSHIHRLQNLTIDILVYDNHVHVARSLKVGSFLR IYSLHTKLQSMNSENQTMLSLEFHLHGGTSYGRGIRVLPESNSDVDQLKKDLESANLTAN QHSDVICQSEPDDSFPSSGSVSLYEVERCQQLSATILTDHQYLERTPLCAILKQKAPQQY RIRAKLRSYKPRRLFQSVKLHCPKCHLLQEVPHEGDLDIIFQDGATKTPDVKLQNTSLYD SKIWTTKNQKGRKVAVHFVKNNGILPLSNECLLLIEGGTLSEICKLSNKFNSVIPVRSGH EDLELLDLSAPFLIQGTIHHYGCKQCSSLRSIQNLNSLVDKTSWIPSSVAEALGIVPLQY VFVMTFTLDDGTGVLEAYLMDSDKFFQIPASEVLMDDDLQKSVDMIMDMFCPPGIKIDAY PWLECFIKSYNVTNGTDNQICYQIFDTTVAEDVI
Function	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. Is a component of the double-stranded telomeric DNA-binding TRF1 complex which is involved in the regulation of telomere length by cis-inhibition of telomerase. Also acts as a single-stranded telomeric DNA-binding protein and thus may act as a downstream effector of the TRF1 complex and may transduce information about telomere maintenance and/or length to the telomere terminus. 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. Binds to two or more telomeric single-stranded 5'-TTAGGG-3' repeats (G-strand) and with high specificity to a minimal telomeric single-stranded 5'-TAGGGTTAG-3' sequence. Binds telomeric single-stranded sequences internally or at proximity of a 3'-end. Its activity is TERT dependent but it does not increase TERT activity by itself. In contrast, the ACD-POT1 heterodimer enhances telomere elongation by increasing telomerase processivity.
Tissue Specificity	Ubiquitous.
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

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[2]
Angiosarcoma	DISIYS9W	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[7]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[7]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[9]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[10]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[10]
Familial atypical multiple mole melanoma syndrome	DIS2YEKP	Strong	SusceptibilityMutation	[11]
Gastric cancer	DISXGOUK	Strong	Biomarker	[12]
Glioma	DIS5RPEH	Strong	Genetic Variation	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[15]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[16]
Lymphoid leukemia	DIS65TYQ	Strong	Biomarker	[17]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Genetic Variation	[18]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[12]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[19]
Primary cutaneous T-cell lymphoma	DIS35WVW	Strong	Genetic Variation	[20]
Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8	DISDO6AW	Strong	Autosomal dominant	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[23]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[18]
Skin cancer	DISTM18U	Strong	Biomarker	[24]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[25]
Stomach cancer	DISKIJSX	Strong	Biomarker	[12]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[2]
Skin neoplasm	DIS16DDV	moderate	Biomarker	[24]
Squamous cell carcinoma	DISQVIFL	moderate	Genetic Variation	[26]
Tumor predisposition syndrome 3	DISMB41N	Moderate	Autosomal dominant	[27]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[28]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[29]
Cerebroretinal microangiopathy with calcifications and cysts 3	DIS0LJOC	Limited	Autosomal recessive	[27]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[30]
Mesothelioma	DISKWK9M	Limited	Genetic Variation	[31]
Methicillin-resistant staphylococci infection	DIS6DRDZ	Limited	Biomarker	[32]
Obsolete glioma susceptibility 9	DIS26ZPK	Limited	Autosomal dominant	[27]
Thyroid cancer	DIS3VLDH	Limited	Genetic Variation	[33]
Thyroid gland carcinoma	DISMNGZ0	Limited	Genetic Variation	[33]
Thyroid tumor	DISLVKMD	Limited	Genetic Variation	[33]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protection of telomeres protein 1 (POT1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protection of telomeres protein 1 (POT1).	[41]
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6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protection of telomeres protein 1 (POT1).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protection of telomeres protein 1 (POT1).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protection of telomeres protein 1 (POT1).	[37]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protection of telomeres protein 1 (POT1).	[38]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Protection of telomeres protein 1 (POT1).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protection of telomeres protein 1 (POT1).	[40]
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⏷ Show the Full List of 6 Drug(s)

References

1	Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis.Oncotarget. 2015 Sep 22;6(28):25109-20. doi: 10.18632/oncotarget.4668.
2	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.
3	POT1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomas.J Am Heart Assoc. 2019 Sep 17;8(18):e012875. doi: 10.1161/JAHA.119.012875. Epub 2019 Sep 12.
4	Regulation of Telomere Length and Atherosclerosis by Protection of Telomeres 1 Protein.J Nanosci Nanotechnol. 2019 Dec 1;19(12):7953-7959. doi: 10.1166/jnn.2019.16938.
5	Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background.Genome Res. 2015 Nov;25(11):1634-45. doi: 10.1101/gr.194449.115. Epub 2015 Sep 16.
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	The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines.Breast Cancer Res Treat. 2014 Jun;145(3):581-91. doi: 10.1007/s10549-014-2975-x. Epub 2014 May 8.
8	Germline mutations in Protection of Telomeres 1 in two families with Hodgkin lymphoma.Br J Haematol. 2018 May;181(3):372-377. doi: 10.1111/bjh.15203.
9	Telomere 1 (POT1) gene expression and its association with telomerase activity in colorectal tumor samples with different pathological features.Biomed Pharmacother. 2014 Sep;68(7):841-6. doi: 10.1016/j.biopha.2014.08.014. Epub 2014 Aug 20.
10	Expression of hPOT1 in HeLa cells and the probability of gene variation of hpot1 Exon14 in endometrial cancer are much higher than in other cancers.Asian Pac J Cancer Prev. 2012;13(11):5659-63. doi: 10.7314/apjcp.2012.13.11.5659.
11	Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.Nat Genet. 2014 May;46(5):482-6. doi: 10.1038/ng.2941. Epub 2014 Mar 30.
12	Expression of telomere binding proteins in gastric cancer and correlation with clinicopathological parameters.Asia Pac J Clin Oncol. 2011 Dec;7(4):339-45. doi: 10.1111/j.1743-7563.2011.01437.x.
13	Impact of Gln94Glu mutation on the structure and function of protection of telomere 1, a cause of cutaneous familial melanoma.J Biomol Struct Dyn. 2020 Mar;38(5):1514-1524. doi: 10.1080/07391102.2019.1610500. Epub 2019 May 7.
14	Telomeric 3' overhangs in chronic HBV-related hepatitis and hepatocellular carcinoma.Int J Cancer. 2008 Jul 15;123(2):264-272. doi: 10.1002/ijc.23376.
15	Telomere structure and maintenance gene variants and risk of five cancer types.Int J Cancer. 2016 Dec 15;139(12):2655-2670. doi: 10.1002/ijc.30288. Epub 2016 Sep 8.
16	Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.Lung Cancer. 2009 Nov;66(2):157-61. doi: 10.1016/j.lungcan.2009.02.005. Epub 2009 Mar 13.
17	A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia.Nat Genet. 2014 Jan;46(1):56-60. doi: 10.1038/ng.2843. Epub 2013 Dec 1.
18	The wide spectrum of POT1 gene variants correlates with multiple cancer types.Eur J Hum Genet. 2017 Nov;25(11):1278-1281. doi: 10.1038/ejhg.2017.134. Epub 2017 Aug 30.
19	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.
20	Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma.JAMA Dermatol. 2019 May 1;155(5):604-609. doi: 10.1001/jamadermatol.2018.3662.
21	POT1 recruits and regulates CST-Pol/Primase at human telomeres. bioRxiv [Preprint]. 2023 Oct 26:2023.05.08.539880. doi: 10.1101/2023.05.08.539880.
22	Genome-wide association study identifies multiple risk loci for renal cell carcinoma.Nat Commun. 2017 Jun 9;8:15724. doi: 10.1038/ncomms15724.
23	Altered expression of TPP1 in fibroblast-like synovial cells might be involved in the pathogenesis of rheumatoid arthritis.Rheumatol Int. 2012 Aug;32(8):2503-10. doi: 10.1007/s00296-011-1992-x. Epub 2011 Jul 16.
24	POT1 loss-of-function variants predispose to familial melanoma.Nat Genet. 2014 May;46(5):478-481. doi: 10.1038/ng.2947. Epub 2014 Mar 30.
25	Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers.Environ Health. 2018 May 2;17(1):43. doi: 10.1186/s12940-018-0387-9.
26	Genetic variants in telomere-maintaining genes and skin cancer risk.Hum Genet. 2011 Mar;129(3):247-53. doi: 10.1007/s00439-010-0921-5. Epub 2010 Nov 30.
27	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.
28	Investigation of deleterious effects of nsSNPs in the POT1 gene: a structural genomics-based approach to understand the mechanism of cancer development.J Cell Biochem. 2019 Jun;120(6):10281-10294. doi: 10.1002/jcb.28312. Epub 2018 Dec 16.
29	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.
30	POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia.Nat Genet. 2013 May;45(5):526-30. doi: 10.1038/ng.2584. Epub 2013 Mar 17.
31	CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.Cancer Lett. 2016 Aug 10;378(2):120-30. doi: 10.1016/j.canlet.2016.05.011. Epub 2016 May 12.
32	Genetic shifts in methicillin-resistant Staphylococcus aureus epidemic clones and toxin gene profiles in Japan: comparative analysis among pre-epidemic, epidemic and post-epidemic phases.J Med Microbiol. 2018 Mar;67(3):392-399. doi: 10.1099/jmm.0.000687. Epub 2018 Feb 2.
33	A new POT1 germline mutation-expanding the spectrum of POT1-associated cancers.Fam Cancer. 2017 Oct;16(4):561-566. doi: 10.1007/s10689-017-9984-y.
34	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.
35	Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
36	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.
37	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
38	The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
39	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.
40	Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
41	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.