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TEP1 is a protein component of two ribonucleoprotein complexes: vaults and telomerase. The vault-associated small RNA, termed vault RNA (VR), is dependent upon TEP1 for its stable association with vaults, while the association of telomerase RNA with the telomerase complex is independent of TEP1. Both of these small RNAs have been shown to interact with amino acids 1-871 of TEP1 in an indirect yeast three-hybrid assay. To understand the determinants of TEP1-RNA binding, we generated a series of TEP1 deletions and show by yeast three-hybrid assay that the entire Tetrahymena p80 homology region of TEP1 is required for its interaction with both telomerase and VRs. This region is also sufficient to target the protein to the vault particle. Electrophoretic mobility shift assays using the recombinant TEP1 RNA-binding domain (TEP1-RBD) demonstrate that it binds RNA directly, and that telomerase and VRs compete for binding. VR binds weakly to TEP1-RBD in vitro, but mutation of VR sequences predicted to disrupt helices near its central loop enhances binding. Antisense oligonucleotide-directed RNase H digestion of endogenous VR indicates that this region is largely single stranded, suggesting that TEP1 may require access to the VR central loop for efficient binding.

Telomere length (TL), typically measured across a sample of blood cells, has emerged as an exciting potential marker of physiological state and of the costs of investment in growth and reproduction within evolutionary ecology. While there is mounting evidence from studies of wild vertebrates that short TL predicts raised subsequent mortality risk, the relationship between reproductive investment and TL is less clear cut, and previous studies report both negative and positive associations. In this study, we examined the relationship between TL and different aspects of maternal reproductive performance in a free‐living population of Soay sheep. We find evidence for shorter TL in females that bred, and thus paid any costs of gestation, compared to females that did not breed. However, we found no evidence for any association between TL and litter size. Furthermore, females that invested in gestation and lactation actually had longer TL than females who only invested in gestation because their offspring died shortly after birth. We used multivariate models to decompose these associations into among‐ and within‐individual effects, and discovered that within‐individual effects were driving both the negative association between TL and gestation, and the positive association between TL and lactation. This suggests that telomere dynamics may reflect recent physiologically costly investment or variation in physiological condition, depending on the aspect of reproduction being investigated. Our results highlight the physiological complexity of vertebrate reproduction, and the need to better understand how and why different aspects of physiological variation underpinning life histories impact blood cell TL. [ABSTRACT FROM AUTHOR]

Telomeres are essential features of linear genomes that are crucial for chromosome stability. Telomeric DNA is usually replenished by telomerase. Deletion of genes encoding telomerase components leads to telomere attrition with each cycle of DNA replication, eventually causing cell senescence or death. In the Saccharomyces cerevisiae strain W303, telomerase-null populations bypass senescence and, unless EXO1 is also deleted, this survival is RAD52 dependent. Unexpectedly, we found that the S. cerevisiae strain $288C could survive the removal of RAD52 and telomerase at a low frequency without additional gene deletions. These RAD52-independent survivors were propagated stably and exhibited a telomere organization typical of recombination between telomeric DNA tracts, and in diploids behaved as a multigenic trait. The polymerase-[delta] subunit Po132 was dispensable for the maintenance of RAD52-independent survivors. The incidence of this rare escape was not affected by deletion of other genes necessary for RAD52-dependent survival, but correlated with initial telomere length. If W303 strains lacking telomerase and RAD52 first underwent telomere elongation, rare colonies could then bypass senescence. We suggest that longer telomeres provide a more proficient substrate for a novel telomere maintenance mechanism that does hot rely on telomerase, RAD52, or POL32. DOI: 10.1534/genetics.109.102939

Telomere shortening and apoptosis are discussed as seen in telomerase-inhibited human tumor cells. The role of telomerase activity in proliferation of human tumor and immortal cells has been looked at using inhibition of telomerase reverse transcriptase (TERT) function. Stable cell lines were generated in two telomerase-positive human cell lines to look at effects of long-term expression of the dominant-negative mutants on tumor cells.

There has been an increasing interest in natural products with the ability to inhibit telomerase activity in tumour and cancerous cells. Green tea catechins have been reported previously to inhibit telomerase, but it was unknown whether catechins from other plant sources could exhibit this property. We isolated 2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (catechin without the presence of a galloyl unit) from the stem bark of B. africana, and tested its ability to inhibit recombinant, partially purified telomerase produced in rabbit reticulocyte lysates. The B. africana catechin inhibited the telomere extension activity of telomerase with an IC50 of approximately 4.7 µg/ml. This finding indicates that the galloyl unit may not be solely responsible for the inhibition of telomerase activity by catechins. This is the first report of the telomerase-inhibiting potential of catechin from the stem bark of B. africana. [ABSTRACT FROM AUTHOR]