A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae.

Wotton, David; Shore, David

doi:10.1101/gad.11.6.748

Cited by 388 publications

(460 citation statements)

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“…5A). Previously, it was found that Rif2 and Rif1 have synergistic effects in inhibiting telomerase (Wotton & Shore, 1997; Levy & Blackburn, 2004) and yet opposing effects in regulating the proliferation of telomere‐dysfunctional cdc13‐1 cells (Addinall et al ., 2008; Xue et al ., 2011). In conclusion, Rif1 is unique among many telomere‐associated proteins in facilitating proliferation of cells lacking telomeres, whereas Rif2 and Mre11 have the opposite effect to Rif1.…”

Section: Resultsmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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SummaryTelomere attrition is linked to cancer, diabetes, cardiovascular disease and aging. This is because telomere losses trigger further genomic modifications, culminating with loss of cell function and malignant transformation. However, factors regulating the transition from cells with short telomeres, to cells with profoundly altered genomes, are little understood. Here, we use budding yeast engineered to lack telomerase and other forms of telomere maintenance, to screen for such factors. We show that initially, different DNA damage checkpoint proteins act together with Exo1 and Mre11 nucleases, to inhibit proliferation of cells undergoing telomere attrition. However, this situation changes when survivors lacking telomeres emerge. Intriguingly, checkpoint pathways become tolerant to loss of telomeres in survivors, yet still alert to new DNA damage. We show that Rif1 is responsible for the checkpoint tolerance and proliferation of these survivors, and that is also important for proliferation of cells with a broken chromosome. In contrast, Exo1 drives extensive genomic modifications in survivors. Thus, the conserved proteins Rif1 and Exo1 are critical for survival and evolution of cells with lost telomeres.

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Section: Resultsmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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“…Deletion of either RIF1 or RIF2, which encode negative regulators of this pathway that interact directly with Rap1 (Hardy et al 1992;Wotton and Shore 1997), causes a telomere elongation phenotype that is considerably exacerbated by the presence of the pol12-216 mutation (Fig. 6C).…”

Section: Telomere Elongation In Pol12-216 Mutants Requires Telomerasementioning

confidence: 99%

“…Maintenance of telomere length about a fixed average value is achieved through a mechanism that appears to measure not the TG-repeat tract length per se, but, rather, the number of Rap1 proteins bound to it (Marcand et al 1997;Ray and Runge 1999a). The C terminus of Rap1 negatively regulates telomere elongation in cis (Kyrion et al 1992;Marcand et al 1996), a function that requires two additional proteins, Rif1 and Rif2, both of which interact physically with this domain of Rap1 (Hardy et al 1992;Moretti et al 1994;Wotton and Shore 1997). The inhibition of telomerase addition by Rap1-Rif1/2 complexes increases linearly as a function of telomere tract length (and presumably the number of Rap1-Rif1/2 complexes bound) through a mechanism that is at present unknown.…”

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confidence: 99%

Pol12, the B subunit of DNA polymerase α, functions in both telomere capping and length regulation

Grossi¹,

Puglisi²,

Dmitriev³

et al. 2004

Genes Dev.

128

173

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The regulation of telomerase action, and its coordination with conventional DNA replication and chromosome end "capping," are still poorly understood. Here we describe a genetic screen in yeast for mutants with relaxed telomere length regulation, and the identification of Pol12, the B subunit of the DNA polymerase ␣ (Pol1)-primase complex, as a new factor involved in this process. Unlike many POL1 and POL12 mutations, which also cause telomere elongation, the pol12-216 mutation described here does not lead to either reduced Pol1 function, increased telomeric single-stranded DNA, or a reduction in telomeric gene silencing. Instead, and again unlike mutations affecting POL1, pol12-216 is lethal in combination with a mutation in the telomere end-binding and capping protein Stn1. Significantly, Pol12 and Stn1 interact in both two-hybrid and biochemical assays, and their synthetic-lethal interaction appears to be caused, at least in part, by a loss of telomere capping. These data reveal a novel function for Pol12 and a new connection between DNA polymerase ␣ and Stn1. We propose that Pol12, together with Stn1, plays a key role in linking telomerase action with the completion of lagging strand synthesis, and in a regulatory step required for telomere capping.

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“…Artificially targeting Rap1p to an individual telomere proportionately shortens the TG 1-3 tract in cis (25,26). This negative regulation requires Rif1p and Rif2p, proteins that bind to the C terminus of Rap1p and play overlapping, but not fully redundant, roles in telomere length homeostasis (13,19,41). The deletion of RIF1 or RIF2 increases the frequency of telomere elongation during a single cell cycle, suggesting that the Rap1p/ Rif1p/Rif2p complex modulates telomerase access in a manner responsive to telomere length (39).…”

mentioning

confidence: 99%

Yeast Est2p Affects Telomere Length by Influencing Association of Rap1p with Telomeric Chromatin

Adkins

Cartwright

et al. 2008

Molecular and Cellular Biology

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In Saccharomyces cerevisiae, the sequence-specific binding of the negative regulator Rap1p provides a mechanism to measure telomere length: as the telomere length increases, the binding of additional Rap1p inhibits telomerase activity in cis. We provide evidence that the association of Rap1p with telomeric DNA in vivo occurs in part by sequence-independent mechanisms. Specific mutations in EST2 (est2-LT) reduce the association of Rap1p with telomeric DNA in vivo. As a result, telomeres are abnormally long yet bind an amount of Rap1p equivalent to that observed at wild-type telomeres. This behavior contrasts with that of a second mutation in EST2 (est2-up34) that increases bound Rap1p as expected for a strain with long telomeres. Telomere sequences are subtly altered in est2-LT strains, but similar changes in est2-up34 telomeres suggest that sequence abnormalities are a consequence, not a cause, of overelongation. Indeed, est2-LT telomeres bind Rap1p indistinguishably from the wild type in vitro. Taken together, these results suggest that Est2p can directly or indirectly influence the binding of Rap1p to telomeric DNA, implicating telomerase in roles both upstream and downstream of Rap1p in telomere length homeostasis.Telomeres are nucleoprotein structures that protect chromosome ends from nucleolytic digestion and preclude the recognition of normal ends as double-strand breaks (6). In most eukaryotes, telomeres are maintained by telomerase, a ribonucleoprotein that uses a short region of its RNA subunit as a template for reverse transcription. In Saccharomyces cerevisiae, a reverse transcriptase (RT) (EST2) and RNA subunit (TLC1) form the catalytic core of telomerase (18,21,35). Est2p contains at least three functional domains: an N-terminal TEN domain that anchors Est2p on its DNA substrate (23,24) and that may interact with other protein components (10), an RNA binding (RBD) region associates with that TLC1 RNA and contributes to dimerization (20), and an RT domain conserved among other telomerases and viral RTs (21).While many organisms synthesize perfect TG-rich telomeric repeats, several protozoa, fungi, slime molds, and plants have heterogeneous telomere sequences (40). S. cerevisiae displays considerable degeneracy, with a consensus of 5Ј-[(TG) 0-6 TG GGTGTG(G)] n (9). Several models have been proposed to explain this heterogeneity. An analysis of wild-type (WT) telomeres and telomeres generated in the presence of template mutations suggests that the registration of the telomere terminus occurs preferentially at the 3Ј end of the template, with processive synthesis through a central core region and decreasing processivity at the 5Ј end of the template (9, 33). In contrast, telomere junction fragments generated during chromosome healing events are more consistent with nonprocessive synthesis and patterning driven by substrate/template alignment (32). In humanized yeast cells, in which the yeast RNA template is replaced with that of humans, Est2p generates perfect hexanucleotide repeats, suggesting that the...

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A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae.

Cited by 388 publications

References 54 publications

Rif1 and Exo1 regulate the genomic instability following telomere losses

Rif1 and Exo1 regulate the genomic instability following telomere losses

Pol12, the B subunit of DNA polymerase α, functions in both telomere capping and length regulation

Yeast Est2p Affects Telomere Length by Influencing Association of Rap1p with Telomeric Chromatin

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