Telomere Length Homeostasis Is Achieved via a Switch between Telomerase- Extendible and -Nonextendible States

Teixeira, Maria Teresa; Arneric, Milica; Sperisen, Peter; Lingner, Joachim

doi:10.1016/s0092-8674(04)00334-4

Cited by 459 publications

(595 citation statements)

References 76 publications

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“…Thus, the shelterin complex so far has been mostly linked to telomerase inhibition. However, telomeres must switch from nonextendible to extendible states, at least in telomerase-positive cells (3,18). Now, both new papers strengthen the view that shelterin components also have a telomerase-activating function.…”

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confidence: 83%

Telomerase Unplugged

2007

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Telomerase Unplugged

2007

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“…To determine whether the catalytic activity of telomerase was required to protect telomeres in cells that utilized the ALT mechanism, we expressed the catalytic component of telomerase (hTERT) in GM847 cells (GM847-hTERT) (Figure 3a) (Hahn et al, 1999). Expression of hTERT reconstitutes telomerase activity in these cells, leading to lengthening of the shortest telomeres (Grobelny et al, 2001;Hemann et al, 2001;Perrem et al, 2001;Teixeira et al, 2004).…”

Section: Flap Endonuclease 1 Depletion In Telomerase-positive Cells Dmentioning

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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“…Examination of the consensus sequence representing yeast telomeres, [(TG) 0-6 TGGGTGTG(G)], reveals that despite the heterogeneity, yeast telomeres always contain a consensus Cdc13 recognition site (that is, a G 1 X 2 G 3 T 4 sequence followed by GTrich sequence). Inspection of several typical yeast telomere sequences (40), shown in Figure 6, reveals that there are many potential binding sites for the Cdc13-DBD contained within the telomere sequence. Thus, the specificity exhibited by the Cdc13-DBD is therefore ideally suited for Cdc13 to fulfill its essential role at the yeast telomere, as a consensus binding sequence is invariably present.…”

Section: Recognition Of Heterogeneous Yeast Telomere Sequencesmentioning

confidence: 99%

“…Wild-type data is shown in circles, inosine with diamonds, A, C and T are shown in squares, traditional triangles, and upside down triangles, respectively. Potential Cdc13 binding sites mapped on representative yeast telomere sequences (40). Multiple Cdc13 binding sites are in every heterogeneous telomere sequence.…”

Section: Recognition Of Heterogeneous Yeast Telomere Sequencesmentioning

confidence: 99%

Identification of the Determinants for the Specific Recognition of Single-Strand Telomeric DNA by Cdc13

2005

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The single-strand overhang present at all known telomeres plays a critical role in mediating both the capping and telomerase regulation functions of telomeres. The telomere end-binding proteins, Cdc13 in S. cerevisiae, Pot1 in higher eukaryotes, and TEBP in the ciliated protozoa O. nova, exhibit sequence-specific binding to their respective single-strand overhangs. S. cerevisiae telomeres are composed of a heterogeneous mixture of GT-rich telomeric sequence, unlike in higher eukaryotes which have a simple repeat that is maintained with high fidelity. In yeast, the telomeric overhang is recognized by the essential protein Cdc13, which coordinates end-capping and telomerase activities at the telomere. The Cdc13-DNA-binding domain (Cdc13-DBD) binds these telomere sequences with high affinity (3 pM) and sequence specificity. To better understand the basis for this remarkable recognition, we have investigated the binding of the Cdc13-DBD to a series of altered DNA substrates. Although an 11-mer of GT-rich sequence is required for full binding affinity, only 3 of these 11 bases are recognized with high specificity. This specificity differs from that observed in the other known telomere end-binding proteins, but is well suited to the specific role of Cdc13 at yeast telomeres. These studies expand our understanding of telomere recognition by the Cdc13-DBD and of the unique molecular recognition properties of ssDNA binding.Recognition of single-strand DNA (ssDNA) is essential for many fundamental cellular activities, including recombination, repair, replication, transcription, translation, and telomere maintenance. Structural and biochemical studies of the proteins that mediate ssDNA-binding activity have provided key insights into the mechanism of recognition. Generally, small domains containing mixed α/β topologies, such as the OB-fold and KH domain, are used for ssDNA recognition, and binding is achieved through base and backbone interactions that are completely distinct from those used in double-strand DNA recognition (1-5). In many biological contexts DNA needs to be uniformly recognized, thus it is appropriate for this recognition to be non-sequence specific. However, in a few cases, including telomere maintenance, transcription, and viral packaging, it is imperative that recognition be exquisitely sequence specific (3,(6)(7)(8).Telomeres, the DNA, RNA and protein complexes at the ends of chromosomes, play important roles in many essential cellular functions. They regulate the proliferative lifetime of the cell and protect chromosomes from degradation or end-to-end fusion, as well as participate in meiotic segregation and chromatic silencing (reviewed in (9-13)). Telomeres are critical to the maintenance of the genome and normal development. Thus, telomere malfunction can have dramatic adverse impacts on human health, leading to cancer, aging disorders and increased human mortality (14)(15)(16)(17)(18)(19). Therefore, it is essential to understand the mechanisms through which telomeres are properly maintain...

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Telomere Length Homeostasis Is Achieved via a Switch between Telomerase- Extendible and -Nonextendible States

Cited by 459 publications

References 76 publications

Telomerase Unplugged

Telomerase Unplugged

FEN1 contributes to telomere stability in ALT-positive tumor cells

Identification of the Determinants for the Specific Recognition of Single-Strand Telomeric DNA by Cdc13

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