| Structural highlights
Disease
[TERT_HUMAN] Note=Activation of telomerase has been implicated in cell immortalization and cancer cell pathogenesis. Defects in TERT are associated with susceptibilty to aplastic anemia (AA) [MIM:609135]. AA is a rare disease in which the reduction of the circulating blood cells results from damage to the stem cell pool in bone marrow. In most patients, the stem cell lesion is caused by an autoimmune attack. T-lymphocytes, activated by an endogenous or exogenous, and most often unknown antigenic stimulus, secrete cytokines, including IFN-gamma, which would in turn be able to suppress hematopoiesis.[1] [2] [3] [4] Note=Genetic variations in TERT are associated with coronary artery disease (CAD).[5] Defects in TERT are the cause of dyskeratosis congenita autosomal dominant type 2 (DKCA2) [MIM:613989]. A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy.[6] [7] Defects in TERT are the cause of pulmonary fibrosis, and/or bone marrow failure, telomere-related, type 1 (PFBMFT1) [MIM:614742]. A disease associated with shortened telomeres. Pulmonary fibrosis is the most common manifestation. Other manifestations include aplastic anemia due to bone marrow failure, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome and acute myeloid leukemia. Phenotype, age at onset, and severity are determined by telomere length. infections, fatal pulmonary complications, or malignancy.[8] [9] [10] [11] [12] Defects in TERT are the cause of dyskeratosis congenita autosomal recessive type 4 (DKCB4) [MIM:613989]. A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. Defects in TERT are a cause of susceptibility to pulmonary fibrosis idiopathic (IPF) [MIM:178500]. Pulmonary fibrosis is a lung disease characterized by shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees of inflammation and fibrosis on biopsy. It results in acute lung injury with subsequent scarring and endstage lung disease.
Function
[TERT_HUMAN] Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis.[13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Publication Abstract from PubMed
Naturally occurring mutations in the ribonucleoprotein reverse transcriptase, telomerase, are associated with the bone marrow failure syndromes dyskeratosis congenita (DKC), aplastic anemia (AA), and idiopathic pulmonary fibrosis (IPF). However, the mechanism by which these mutations impact telomerase function remains unknown. Here we present the structure of the human telomerase c-terminal extension (CTE or thumb domain) determined by the method of single-wavelength anomalous diffraction (SAD) to 2.31 A resolution. We also used direct telomerase activity and nucleic acid binding assays to explain how naturally occurring mutations within this portion of telomerase contribute to human disease. The single mutations localize within three highly conserved regions of the telomerase thumb domain referred to as motifs E-I, (thumb loop and helix) E-II and E-III (the FVYL pocket, comprising the hydrophobic residues F1012, V1025, Y1089 and L1092). Biochemical data shows that the mutations associated with DKC, AA and IFP disrupt the binding between telomerases protein subunit reverse transcriptase (TERT) and its nucleic acid substrates leading to loss of telomerase activity and processivity. Collectively our data shows that although these mutations do not alter the overall stability or expression of TERT, these rare genetic disorders are associated with an impaired telomerase holoenzyme that is unable to correctly assemble with its nucleic acid substrates, leading to incomplete telomere extension and telomere attrition, which are hallmarks of these diseases.
Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Telomerase-Associated Bone Marrow Failure Syndromes.,Hoffman H, Rice C, Skordalakes E J Biol Chem. 2017 Feb 1. pii: jbc.M116.771204. doi: 10.1074/jbc.M116.771204. PMID:28154186[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis. 2005 May-Jun;34(3):257-63. PMID:15885610 doi:10.1016/j.bcmd.2004.12.008
- ↑ Liang J, Yagasaki H, Kamachi Y, Hama A, Matsumoto K, Kato K, Kudo K, Kojima S. Mutations in telomerase catalytic protein in Japanese children with aplastic anemia. Haematologica. 2006 May;91(5):656-8. Epub 2006 Apr 19. PMID:16627250
- ↑ Xin ZT, Beauchamp AD, Calado RT, Bradford JW, Regal JA, Shenoy A, Liang Y, Lansdorp PM, Young NS, Ly H. Functional characterization of natural telomerase mutations found in patients with hematologic disorders. Blood. 2007 Jan 15;109(2):524-32. Epub 2006 Sep 21. PMID:16990594 doi:10.1182/blood-2006-07-035089
- ↑ Kirwan M, Vulliamy T, Marrone A, Walne AJ, Beswick R, Hillmen P, Kelly R, Stewart A, Bowen D, Schonland SO, Whittle AM, McVerry A, Gilleece M, Dokal I. Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum Mutat. 2009 Nov;30(11):1567-73. doi: 10.1002/humu.21115. PMID:19760749 doi:10.1002/humu.21115
- ↑ Matsubara Y, Murata M, Watanabe K, Saito I, Miyaki K, Omae K, Ishikawa M, Matsushita K, Iwanaga S, Ogawa S, Ikeda Y. Coronary artery disease and a functional polymorphism of hTERT. Biochem Biophys Res Commun. 2006 Sep 22;348(2):669-72. Epub 2006 Jul 28. PMID:16890917 doi:10.1016/j.bbrc.2006.07.103
- ↑ Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis. 2005 May-Jun;34(3):257-63. PMID:15885610 doi:10.1016/j.bcmd.2004.12.008
- ↑ Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15960-4. Epub 2005 Oct 24. PMID:16247010 doi:0508124102
- ↑ Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005 Apr 7;352(14):1413-24. PMID:15814878 doi:10.1056/NEJMoa042980
- ↑ Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7552-7. Epub 2007 Apr 25. PMID:17460043 doi:10.1073/pnas.0701009104
- ↑ Parry EM, Alder JK, Qi X, Chen JJ, Armanios M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood. 2011 May 26;117(21):5607-11. doi: 10.1182/blood-2010-11-322149. Epub 2011 , Mar 24. PMID:21436073 doi:10.1182/blood-2010-11-322149
- ↑ Alder JK, Cogan JD, Brown AF, Anderson CJ, Lawson WE, Lansdorp PM, Phillips JA 3rd, Loyd JE, Chen JJ, Armanios M. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genet. 2011 Mar;7(3):e1001352. doi: 10.1371/journal.pgen.1001352. Epub 2011 , Mar 31. PMID:21483807 doi:10.1371/journal.pgen.1001352
- ↑ Gansner JM, Rosas IO, Ebert BL. Pulmonary fibrosis, bone marrow failure, and telomerase mutation. N Engl J Med. 2012 Apr 19;366(16):1551-3. doi: 10.1056/NEJMc1200999. PMID:22512499 doi:10.1056/NEJMc1200999
- ↑ Harrington L, Zhou W, McPhail T, Oulton R, Yeung DS, Mar V, Bass MB, Robinson MO. Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes Dev. 1997 Dec 1;11(23):3109-15. PMID:9389643
- ↑ Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler S. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res. 2004 Apr 2;94(6):768-75. Epub 2004 Feb 12. PMID:14963003 doi:10.1161/01.RES.0000121104.05977.F3
- ↑ Moriarty TJ, Marie-Egyptienne DT, Autexier C. Functional organization of repeat addition processivity and DNA synthesis determinants in the human telomerase multimer. Mol Cell Biol. 2004 May;24(9):3720-33. PMID:15082768
- ↑ Moriarty TJ, Ward RJ, Taboski MA, Autexier C. An anchor site-type defect in human telomerase that disrupts telomere length maintenance and cellular immortalization. Mol Biol Cell. 2005 Jul;16(7):3152-61. Epub 2005 Apr 27. PMID:15857955 doi:10.1091/mbc.E05-02-0148
- ↑ Rahman R, Mo L, Cui W. Telomerase with mutated catalytic motifs has dominant negative effects on telomerase activity and inhibits cell growth. Biochem Biophys Res Commun. 2006 Nov 24;350(3):796-802. Epub 2006 Sep 29. PMID:17026956 doi:10.1016/j.bbrc.2006.09.125
- ↑ Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol. 2007 Jun 15;178(12):7710-9. PMID:17548608
- ↑ Wyatt HD, Lobb DA, Beattie TL. Characterization of physical and functional anchor site interactions in human telomerase. Mol Cell Biol. 2007 Apr;27(8):3226-40. Epub 2007 Feb 12. PMID:17296728 doi:10.1128/MCB.02368-06
- ↑ Drosopoulos WC, Prasad VR. The active site residue Valine 867 in human telomerase reverse transcriptase influences nucleotide incorporation and fidelity. Nucleic Acids Res. 2007;35(4):1155-68. Epub 2007 Jan 30. PMID:17264120 doi:10.1093/nar/gkm002
- ↑ Ram R, Uziel O, Eldan O, Fenig E, Beery E, Lichtenberg S, Nordenberg Y, Lahav M. Ionizing radiation up-regulates telomerase activity in cancer cell lines by post-translational mechanism via ras/phosphatidylinositol 3-kinase/Akt pathway. Clin Cancer Res. 2009 Feb 1;15(3):914-23. doi: 10.1158/1078-0432.CCR-08-0792. PMID:19188162 doi:10.1158/1078-0432.CCR-08-0792
- ↑ Oh W, Ghim J, Lee EW, Yang MR, Kim ET, Ahn JH, Song J. PML-IV functions as a negative regulator of telomerase by interacting with TERT. J Cell Sci. 2009 Aug 1;122(Pt 15):2613-22. doi: 10.1242/jcs.048066. Epub 2009 Jun, 30. PMID:19567472 doi:10.1242/jcs.048066
- ↑ Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009 Jul 2;460(7251):66-72. doi: 10.1038/nature08137. PMID:19571879 doi:10.1038/nature08137
- ↑ Wyatt HD, Tsang AR, Lobb DA, Beattie TL. Human telomerase reverse transcriptase (hTERT) Q169 is essential for telomerase function in vitro and in vivo. PLoS One. 2009 Sep 24;4(9):e7176. doi: 10.1371/journal.pone.0007176. PMID:19777057 doi:10.1371/journal.pone.0007176
- ↑ Hoffman H, Rice C, Skordalakes E. Structural Analysis Reveals the Deleterious Effects of Telomerase Mutations in Telomerase-Associated Bone Marrow Failure Syndromes. J Biol Chem. 2017 Feb 1. pii: jbc.M116.771204. doi: 10.1074/jbc.M116.771204. PMID:28154186 doi:http://dx.doi.org/10.1074/jbc.M116.771204
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