Progressive cis-inhibition of telomerase upon telomere elongation

Marcand, Stéphane; Brevet, Vanessa; Gilson, Éric

doi:10.1093/emboj/18.12.3509

Cited by 194 publications

(270 citation statements)

References 77 publications

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“…The increased processivity requires Tel1. The telomere-shortening rate in the absence of telomerase is length-independent (Marcand et al 1999). The observed increased frequency of telomere elongation by telomerasewith telomere shortening is sufficient to explain telomere length homeostasis.…”

Section: Telomere Replicationmentioning

confidence: 91%

Replication of Telomeres and the Regulation of Telomerase

Pfeiffer

Lingner

2013

Cold Spring Harbor Perspectives in Biology

112

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Telomeres are the physical ends of eukaryotic chromosomes. They protect chromosome ends from DNA degradation, recombination, and DNA end fusions, and they are important for nuclear architecture. Telomeres provide a mechanism for their replication by semiconservative DNA replication and length maintenance by telomerase. Through telomerase repression and induced telomere shortening, telomeres provide the means to regulate cellular life span. In this review, we introduce the current knowledge on telomere composition and structure. We then discuss in depth the current understanding of how telomere components mediate their function during semiconservative DNA replication and how telomerase is regulated at the end of the chromosome. We focus our discussion on the telomeres from mammals and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe.

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Section: Telomere Replicationmentioning

confidence: 91%

Replication of Telomeres and the Regulation of Telomerase

Pfeiffer

Lingner

2013

Cold Spring Harbor Perspectives in Biology

112

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“…Depletion of FEN1 appears to exacerbate telomere dysfunction by producing signal-free ends in fibroblasts (Saharia et al, 2008) and increasing the number of TIFs in ALT cells ( Figures 1d and e), thus leading to additional substrates capable of participating in end-to-end fusions. As telomerase acts on the shortest telomeres (Marcand et al, 1999;Forstemann et al, 2000;Ouellette et al, 2000), it would be recruited to those chromosome ends that experienced a catastrophic loss because of a stalled and unresolved replication fork or failure to cap the telomere. Telomerase could then extend the short telomeres, stabilizing them and rescuing telomere dysfunction.…”

Section: Role Of Fen1 In Alt Tumor Cells a Saharia And Sa Stewartmentioning

confidence: 99%

FEN1 contributes to telomere stability in ALT-positive tumor cells

Saharia

Stewart

2009

Oncogene

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Abrogation of telomere stability through loss-of-function mutations in telomere binding proteins contributes to genomic instability and cancer progression. Recently, Flap endonuclease 1 (FEN1) was shown to contribute to telomere stability in human cells that had not yet activated a telomere maintenance mechanism, suggesting that abrogation of FEN1 function influences the transformation process by compromising telomere stability and driving genomic instability. Here, we analyse the telomeres in human cancer cells following FEN1 depletion. We show that FEN1 is required for telomere stability in cells that rely on the alternative lengthening of telomere (ALT) mechanism. Indeed, FEN1 depletion resulted in telomere dysfunction, characterized by formation of telomere dysfunction-induced foci (TIFs) and end-to-end fusions in ALT-positive cells. In contrast, no telomere phenotype was observed in telomerase-positive cells on FEN1 depletion, suggesting that ongoing telomerase activity protected telomeres. In consonance with this, we found that expression of the catalytic component of telomerase (hTERT) but not an inactive allele rescued telomere dysfunction on FEN1 depletion in ALT cells. Our data suggest that mutations that arise in FEN1 affect telomere stability and genome fidelity by promoting telomere fusions and anaphase-bridge-breakage cycles, which further drive genome instability and thereby contribute to the transformation process.

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“…In an attempt to directly address whether Sba1p is required for telomere lengthening in vivo, we exploited an established system to determine the extension rates of a shortened telomere in WT and sba1⌬ yeast. In brief, the left arm terminus of chromosome VII contains an internal telomere tract that is flanked by Flp1p-recognition target (FRT) sites, the tract can be specifically removed upon the transient Flp1p expression and changes in length can be monitored during subsequent growth by Southern blot analysis (17,18). Using this system we determined the telomere extension rates in WT and sba1⌬ yeast and found that the sba1⌬ rate was 50% of WT after 3 generations and remained at 65% after 6 and 10 generations of growth (Fig.…”

Section: Fig 4 In Vivo Levels Of Sba1p Affect Telomere Occupancy Bymentioning

confidence: 99%

The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation

Toogun

Zeiger

Freeman

2007

Proc. Natl. Acad. Sci. U.S.A.

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Telomeres are the composite of short DNA element tandem arrays and heterotypic protein components that protect and maintain chromosomal termini. As proper telomere maintenance requires a multitude of DNA extension events, it is important to understand the factors that modulate telomerase DNA association. Here, we show that the endogenous levels of the yeast p23 molecular chaperone Sba1p are required for telomere length maintenance and that Sba1p can modulate telomerase DNA binding and extension activities in vitro. Notably, telomere occupancy by telomerase and the extension rate of a shortened telomere fluctuated with changing Sba1 protein levels in vivo. In addition, we found that Sba1p displayed a cell cycle-dependent telomere interaction that paralleled telomerase binding; telomere association by Sba1p depended on its inherent chaperone activity. Taken together, our results support a model in which Sba1p modulates telomerase DNA binding activity for optimal function in vitro and in vivo. DNA protein dynamicsT elomerase maintains genomic integrity, in part, by preserving chromosome length after DNA replication (1-3). Because conventional DNA polymerases require priming events to initiate synthesis, the extreme terminus of each lagging strand cannot be completed, which is commonly referred to as the end replication problem (4). In the absence of a compensatory process, this limitation would lead to chromosome erosion with each round of DNA replication. However, almost all eukaryotes circumvent this problem by adding simple DNA sequence motifs to each terminus that buffers against the loss. Typically the DNA motifs are added by the specialized ribonucleoprotein complex telomerase that is composed of a reverse transcriptase protein and an associated template RNA; in yeast, EST2 and TLC1 encode these factors. Depending on the organism, telomerase increases chromosome ends between a few hundred to a few thousand nucleotides to create, in part, a telomere. Perhaps unexpectedly, it was realized that the length of each telomere is not added at once but rather telomerase may append 6-8 nt per binding event (5). Although it had been argued that telomerase activity might not need to be iterative to maintain telomere length, recent studies in yeast indicate that telomeres can be extended over 100 nt per cell cycle (6, 7). Unfortunately, yeast telomerase does not add multiple repeats in vitro but rather extends a DNA substrate a single repeat and remains bound in a stalled state (5). Thus, the question is raised about how a bound telomerase complex is removed to allow the redundant binding and addition cycles necessary to support proper telomere maintenance.Prior studies indicated that the p23 and Hsp90 molecular chaperones are required for reconstitution of human telomerase activity in vitro (8, 9); unlike other telomerase cofactors the molecular chaperones seemingly remain associated during reverse transcription (9). A recent study indicates that the Hsp90 interaction might be necessary to promote telomerase DNA binding ...

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Progressive cis-inhibition of telomerase upon telomere elongation

Cited by 194 publications

References 77 publications

Replication of Telomeres and the Regulation of Telomerase

Replication of Telomeres and the Regulation of Telomerase

FEN1 contributes to telomere stability in ALT-positive tumor cells

The p23 molecular chaperone promotes functional telomerase complexes through DNA dissociation

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