TERT Structure, Function, and Molecular Mechanisms

Skordalakes, Emmanuel; Lue, Neal F.

doi:10.1002/9781118268667.ch3

Cited by 3 publications

(5 citation statements)

References 98 publications

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“…Limited Tracts of Uracil in Telomeric DNA Do Not Affect Overall Telomerase Extension-Telomerase recognizes and extends ss DNA primers by virtue of limited primer-template base pairing between telomeric DNA and the telomerase RNA, and by a DNA-binding anchor site within telomerase reverse transcriptase itself (33,34). These and other properties of the enzyme enable it to tolerate substitution of dTTP in the primer without significant impairment of binding or extension (17,(35)(36)(37)(38).…”

Section: Uracil In Telomere Dna Interferes With Binding Of Pot1-mentioning

confidence: 99%

Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells

Vallabhaneni

Zhou

Maul

et al. 2015

Journal of Biological Chemistry

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Section: Uracil In Telomere Dna Interferes With Binding Of Pot1-mentioning

confidence: 99%

Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells

Vallabhaneni

Zhou

Maul

et al. 2015

Journal of Biological Chemistry

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“…the primary structure of the reverse transcriptase domain is similar to the structures of other polymerases and contains seven conserved motifs (1, 2, А, В, С, D, and Е). It is assumed that tert originates from retrotransposons [103]. Intron-containing (the so-called Penelope-like) elements are the ones most similar to tert.…”

Section: Telomerase Structurementioning

confidence: 99%

“…Structures with high-resolution ten and trBD tert domains and full-length tert were recently derived from Tetrahymena thermophila [102,103] and Tribolium castaneum [104], respectively; they showed new features of telomerase structure and function. As follows from the analysis of the structure of tert derived from T. castaneum, high structural homology exists between tert and other polymerases, including the p66 subunit of HIV reverse transcriptase [105].…”

Section: Telomerase Structurementioning

confidence: 99%

“…the cP-motif contains a positively charged pocket, whereas the t-motif is a narrow hydrophobic gap with positively charged residues near the cP-motif. together, they form an extensive groove on the surface of trBD, to which ter is bound [100,103,[116][117][118][119]. the t-motif contains a β-stem-loop stretched in the direction of the c-terminal domain, which forms the "thumb," and links it to the "fingers" of the reverse transcriptase domain.…”

Section: Telomerase Structurementioning

confidence: 99%

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Telomere Lengthening and Other Functions of Telomerase

et al. 2012

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Telomerase is an enzyme that maintains the length of the telomere. The telomere length specifies the number of divisions a cell can undergo before it finally dies (i.e. the proliferative potential of cells). For example, telomerase is activated in embryonic cell lines and the telomere length is maintained at a constant level; therefore, these cells have an unlimited fission potential. Stem cells are characterized by a lower telomerase activity, which enables only partial compensation for the shortening of telomeres. Somatic cells are usually characterized by the absence of telomerase activity. Telomere shortening leads to the attainment of the Hayflick limit, the transition of cells to a state of senescence. The cells subsequently enter a state of crisis, accompanied by massive cell death. The surviving cells become cancer cells, which are capable both of dividing indefinitely and maintaining telomere length (usually with the aid of telomerase). Telomerase is a reverse transcriptase. It consists of two major components: telomerase RNA (TER) and reverse transcriptase (TERT). TER is a non-coding RNA, and it contains the region which serves as a template for telomere synthesis. An increasing number of articles focussing on the alternative functions of telomerase components have recently started appearing. The present review summarizes data on the structure, biogenesis, and functions of telomerase.

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“…hTERT is made up of 4 main functional domains: RT, TEN, TRBD, and CTE. The RT domain functions as the active site and TEN domain functions as an anchor site for the primer and nascent DNA product. − The telomerase reaction cycle has three steps: recognition, elongation, and translocation, followed by repeated rounds of elongation/translocation. During the translocation step telomerase dissociates from the newly synthesized DNA and realigns it with the template to synthesize a new repeat.…”

Section: Introductionmentioning

confidence: 99%

Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays

Talari

Bagherzadeh

Golestanian

et al. 2015

J. Chem. Inf. Model.

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Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational design of telomerase inhibitors was made possible by the determination of high resolution structures of the catalytic telomerase subunit from a beetle and subsequent molecular modeling of the human telomerase complex. A hybrid strategy including docking, pharmacophore-based virtual screening, and molecular dynamics simulations (MDS) were used to identify new human telomerase inhibitors. Docking methodology was applied to investigate the ssDNA telomeric sequence and two well-known human telomerase inhibitors' (BIBR1532 and MST-312) modes of interactions with hTERT TEN domain. Subsequently molecular dynamic simulations were performed to monitor and compare hTERT TEN domain, TEN-ssDNA, TEN-BIBR1532, TEN-MST-312, and TEN-ssDNA-BIBR1532 behavior in a dynamic environment. Pharmacophore models were generated considering the inhibitors manner in the TEN domain anchor site. These exploratory studies identified several new potent inhibitors whose IC50 values were generated experimentally in a low micromolar range with the aid of biochemical assays, including both the direct telomerase and the telomeric repeat amplification protocol (TRAP) assays. The results suggest that the current models of human telomerase are useful templates for rational inhibitor design.

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TERT Structure, Function, and Molecular Mechanisms

Cited by 3 publications

References 98 publications

Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells

Defective Repair of Uracil Causes Telomere Defects in Mouse Hematopoietic Cells

Telomere Lengthening and Other Functions of Telomerase

Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays

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