Journal ArticleDOI
Reverse Transcriptase Motifs in the Catalytic Subunit of Telomerase
Joachim Lingner,Timothy P. Hughes,Andrej Shevchenko,Matthias Mann,Victoria Lundblad,Thomas R. Cech +5 more
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TLDR
The reverse transcriptase protein fold, previously known to be involved in retroviral replication and retrotransposition, is essential for normal chromosome telomere replication in diverse eukaryotes.Abstract:
Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Telomerase RNA components have been identified from many organisms, but no protein component has been demonstrated to catalyze telomeric DNA extension. Telomerase was purified from Euplotes aediculatus, a ciliated protozoan, and one of its proteins was partially sequenced by nanoelectrospray tandem mass spectrometry. Cloning and sequence analysis of the corresponding gene revealed that this 123-kilodalton protein (p123) contains reverse transcriptase motifs. A yeast (Saccharomyces cerevisiae) homolog was found and subsequently identified as EST2 (ever shorter telomeres), deletion of which had independently been shown to produce telomere defects. Introduction of single amino acid substitutions within the reverse transcriptase motifs of Est2 protein led to telomere shortening and senescence in yeast, indicating that these motifs are important for catalysis of telomere elongation in vivo. In vitro telomeric DNA extension occurred with extracts from wild-type yeast but not from est2 mutants or mutants deficient in telomerase RNA. Thus, the reverse transcriptase protein fold, previously known to be involved in retroviral replication and retrotransposition, is essential for normal chromosome telomere replication in diverse eukaryotes.read more
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Journal ArticleDOI
Extension of life-span by introduction of telomerase into normal human cells
Andrea G. Bodnar,Michel M. Ouellette,Maria Frolkis,Shawn E. Holt,Choy-Pik Chiu,Gregg B. Morin,Calvin B. Harley,Jerry W. Shay,Serge Lichtsteiner,Woodring E. Wright +9 more
TL;DR: In this article, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomere catalytic subunit.
Journal ArticleDOI
Telomerase catalytic subunit homologs from fission yeast and human
Toru Nakamura,Gregg B. Morin,Gregg B. Morin,Karen B. Chapman,Karen B. Chapman,Scott L. Weinrich,Scott L. Weinrich,William H. Andrews,William H. Andrews,Joachim Lingner,Joachim Lingner,Calvin B. Harley,Calvin B. Harley,Thomas R. Cech,Thomas R. Cech +14 more
TL;DR: In this paper, the homologous genes from the fission yeast Schizosaccharomyces pombe and human are identified and the proposed telomerase catalytic subunits represent a deep branch in the evolution of reverse transcriptases.
Journal ArticleDOI
Modular regulatory principles of large non-coding RNAs
TL;DR: This work synthesizes studies to provide an emerging model whereby large ncRNAs might achieve regulatory specificity through modularity, assembling diverse combinations of proteins and possibly RNA and DNA interactions.
Journal ArticleDOI
hEST2, the Putative Human Telomerase Catalytic Subunit Gene, Is Up-Regulated in Tumor Cells and during Immortalization
Matthew Meyerson,Christopher M. Counter,Elinor Ng Eaton,Leif W. Ellisen,Philipp Steiner,Stephanie Dickinson Caddle,Liuda Ziaugra,Roderick L. Beijersbergen,Michael J. Davidoff,Qingyun Liu,Silvia Bacchetti,Daniel A. Haber,Robert A. Weinberg +12 more
TL;DR: The cloning of a human gene, hEST2, that shares significant sequence similarity with the telomerase catalytic subunit genes of lower eukaryotes is reported, suggesting that the induction of hEST 2 mRNA expression is required for the telomersase activation that occurs during cellular immortalization and tumor progression.
Journal ArticleDOI
Mobile elements: drivers of genome evolution.
TL;DR: Mobile elements within genomes have driven genome evolution in diverse ways and are becoming useful tools for learning more about genome evolution and gene function.
References
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Journal ArticleDOI
Electrospray ionization for mass spectrometry of large biomolecules
TL;DR: Spectra have been obtained for biopolymers including oligonucleotides and proteins, the latter having molecular weights up to 130,000, with as yet no evidence of an upper limit.
Journal ArticleDOI
The RNA component of human telomerase
Junli Feng,Walter Funk,Sy Shi Wang,Scott L. Weinrich,Ariel A. Avilion,Choy-Pik Chiu,Robert Adams,Edwin Chang,Richard C. Allsopp,Jinghua Yu,Siyuan Le,Michael D. West,Calvin B. Harley,William H. Andrews,Carol W. Greider,Bryant Villeponteau +15 more
TL;DR: Human cell lines that expressed hTR mutated in the template region generated the predicted mutant telomerase activity, and cells transfected with an antisense hTR lost telomeric DNA and began to die after 23 to 26 doublings.
Telomere shortening associated withchromosome instability isarrested inimmortal cells whichexpress telomerase activity
Christopher M. Counter,Ariel A. Avilion,Catherine E. LeFeuvrel,Carol W. Greider,Calvin B. Harley,A. Steitz +5 more
TL;DR: The results suggest that chromosomes with short (TTAGGG)n tracts are recombinogenic, critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization.
Journal ArticleDOI
Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.
Christopher M. Counter,A.A. Avilion,C.E. LeFeuvre,N.G. Stewart,Carol W. Greider,Calvin B. Harley,Silvia Bacchetti +6 more
TL;DR: In this article, the authors measured telomere length, telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5 and found that telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures.
Journal ArticleDOI
Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor.
TL;DR: A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer.