Rif1 and Rif2 Inhibit Localization of Tel1 to DNA Ends

Hirano, Yukinori; Fukunaga, Kenzo; Sugimoto, Katsunori

doi:10.1016/j.molcel.2008.12.027

Cited by 115 publications

(218 citation statements)

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“…We concluded that telomeres can be maintained by telomerase alone in sae2D sgs1D cells, but recombination also contributes to elongate telomeres in these cells. We next asked whether telomerase activity is sensitive to the negative regulation by Rif2, which competes with Tel1 binding at telomeres 27,44 , in the combined absence of Sae2 and Sgs1. We monitored the telomere length of sae2D sgs1D rif2D clones as described in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the action of Rap1/Rif2 limits MRX binding at de novo telomeres 23,24 , whereas Rap1/Rif1 supports the protection function of the CST complex by a yet unknown mechanism 25 . The MRX complex also plays a key role in targeting telomerase to short telomeres 26 by recruiting Tel1 via specific interaction with a conserved motif in the Xrs2 C-terminus [26][27][28] . Finally, owing to a high GC content and the presence of stable protein/DNA complexes, telomeres are a challenge for the replication machinery that might become dependent on a specific set of proteins to avoid fork collapse in telomeric repeats 6,29 .…”

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Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA

et al. 2014

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In budding yeast, DNA ends are processed by the consecutive action of MRX/Sae2 and two redundant pathways dependent on Sgs1/Dna2 and Exo1, and this processing is counteracted by Ku heterodimer. Here we show that DNA end resection by Sae2 and Sgs1 is dispensable for normal telomere maintenance by telomerase. Instead, these proteins facilitate telomere replication and limit the accumulation of single-strand DNA (ssDNA) at replication fork pause sites. Loss of Sae2 and Sgs1 drives selection for compensatory mutations, notably in Ku, which are responsible for abrupt telomere shortening in cells lacking Sae2 and Sgs1. In telomerase-negative cells, Sae2 and Sgs1 play non-overlapping roles in generating ssDNA at eroded telomeres and are required for the formation of type II survivors. Thus, although their primary function in telomerase-positive cells is to sustain DNA replication over the sites that are prone to fork pausing, Sae2 and Sgs1 contribute to telomere resection in telomerase-deficient cells.

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Section: Resultsmentioning

confidence: 99%

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Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA

et al. 2014

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“…The frequency of elongation is regulated by the numberof Rap1/Rif1/Rif2 proteins that are bound to telomeres in dependence of their length (Marcand et al 1997). Mechanistically, this may involve the competition of Rif1/ 2 with Tel1 for binding of the carboxyl terminus of Xrs2 (Hirano et al 2009). Thus, at short telomeres that bind less Rap1/Rif/Rif2, Tel1 recruitment to the MRX complex may be favored, leading to preferential recruitment and activation of telomerase at short telomeres (Fig.…”

Section: Telomere Replicationmentioning

confidence: 99%

Replication of Telomeres and the Regulation of Telomerase

Pfeiffer

Lingner

2013

Cold Spring Harbor Perspectives in Biology

106

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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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“…Rif2 physically interacts with MRX in vitro (26) and inhibits MRXdependent 5=-end resection at telomeres (6,7). Furthermore, the lack of Rif2 enhances MRX and Tel1 association at telomeres (7,26), suggesting that Rif2 regulates nucleolytic processing of telomeres by inhibiting MRX recruitment. However, the artificial tethering of Rif2 at DNA ends leads to decreased Tel1 binding, but not MRX binding, to these ends (26), indicating that Rif2 counteracts Tel1 association to DNA ends.…”

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A Balance between Tel1 and Rif2 Activities Regulates Nucleolytic Processing and Elongation at Telomeres

Martina

Clerici

Baldo

et al. 2012

Molecular and Cellular Biology

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Generation of G-strand overhangs at Saccharomyces cerevisiae yeast telomeres depends primarily on the MRX (Mre11-Rad50-Xrs2) complex, which is also necessary to maintain telomere length by recruiting the Tel1 kinase. MRX physically interacts with Rif2, which inhibits both resection and elongation of telomeres. We provide evidence that regulation of telomere processing and elongation relies on a balance between Tel1 and Rif2 activities. Tel1 regulates telomere nucleolytic processing by promoting MRX activity. In fact, the lack of Tel1 impairs MRX-dependent telomere resection, which is instead enhanced by the Tel1-hy909 mutant variant, which causes telomerase-dependent telomere overelongation. The Tel1-hy909 variant is more robustly associated than wild-type Tel1 to double-strand-break (DSB) ends carrying telomeric repeat sequences. Furthermore, it increases the persistence at a DSB adjacent to telomeric repeats of both MRX and Est1, which in turn likely account for the increased telomere resection and elongation in TEL1-hy909 cells. Strikingly, Rif2 is unable to negatively regulate processing and lengthening at TEL1-hy909 telomeres, indicating that the Tel1-hy909 variant overcomes the inhibitory activity exerted by Rif2 on MRX. Altogether, these findings highlight a primary role of Tel1 in overcoming Rif2-dependent negative regulation of MRX activity in telomere resection and elongation.A highly ordered nucleoprotein complex called the telomere prevents the ends of linear chromosomes from being recognized as DNA double-strand breaks (DSBs) (reviewed in reference 30). Another key function of telomeres is to compensate for the incomplete replication of chromosome ends caused by discontinuous DNA synthesis. In most eukaryotes, telomeric DNA comprises tandemly repeated G-rich sequences (TG 1-3 repeats in Saccharomyces cerevisiae yeast and T 2 AG 3 in vertebrates), ending in a single-stranded 3= overhang (G tail) (reviewed in reference 20). The addition of telomeric repeats depends on the action of telomerase, a specialized reverse transcriptase that extends the TGrich strand of chromosome ends (23). The yeast telomerase complex consists of a reverse transcriptase subunit (Est2), a template RNA (TLC1), and two accessory proteins (Est1 and Est3), which are required for telomerase activity in vivo but not in vitro.The single-stranded G tails of budding yeast telomeres are short (about 10 to 15 nucleotides [nt]) for most of the cell cycle, but their length increases transiently to 50 to 100 nucleotides in late S phase (15, 50). While telomeric G tails can be generated during lagging-strand replication by removal of the last RNA primer, the 5= C strand of the telomere generated by leadingstrand synthesis must be nucleolytically processed (resected) to generate 3= overhangs (32, 51). Cyclin-dependent kinase (Cdk1 in S. cerevisiae) activity is required for this telomeric C-strand resection (17, 49), which occurs only during S and G 2 cell cycle phases, when Cdk1 activity is high and telomeres are elongated by telomerase (36...

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Rif1 and Rif2 Inhibit Localization of Tel1 to DNA Ends

Cited by 115 publications

References 58 publications

Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA

Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA

Replication of Telomeres and the Regulation of Telomerase

A Balance between Tel1 and Rif2 Activities Regulates Nucleolytic Processing and Elongation at Telomeres

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