Cdc13 prevents telomere uncapping and Rad50-dependent homologous recombination

Grandin, Nathalie

doi:10.1093/emboj/20.21.6127

Cited by 80 publications

(113 citation statements)

References 47 publications

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“…4). The mutant mec1⌬ sml1⌬ cdc13-1 had a slight higher permissive temperature (about 29°C), as previously reported (31). However, mec1⌬ sml1⌬ greatly reduced caspase activation (Fig.…”

Section: Mec1 Plays An Important Role In Mediating Apoptoticsupporting

confidence: 86%

Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast

Qi¹,

Li²,

Kuo³

et al. 2003

Journal of Biological Chemistry

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Inactivation of the budding yeast telomere binding protein Cdc13 results in abnormal telomeres (exposed long G-strands) and activation of the DNA damage checkpoint. In the current study, we show that inactivation of Cdc13p induces apoptotic signals in yeast, as evidenced by caspase activation, increased reactive oxygen species production, and flipping of phosphatidylserine in the cytoplasmic membrane. These apoptotic signals were suppressed in a mitochondrial ( o ) mutant. Moreover, mitochondrial proteins (e.g. MTCO3) were identified as multicopy suppressors of cdc13-1, suggesting the involvement of mitochondrial functions in telomere-initiated apoptotic signaling. These telomereinitiated apoptotic signals were also shown to depend on MEC1, but not TEL1, and were antagonized by MRE11. Our results are consistent with a model in which single-stranded G-tails in the cdc13-1 mutant trigger MEC1-dependent apoptotic signaling in yeast.Cdc13p is a budding yeast telomere binding protein (1-3). Cdc13p appears to be a multifunctional protein involved in both telomere replication and protection (1-4). Its role in telomere replication has been suggested based on the findings that it interacts with the catalytic subunit of DNA polymerase ␣ and an essential subunit of telomerase, Est1p (4), and a mutation form of CDC13, cdc13-2, shows the telomerase negative phenotype (3). Its essential role in protecting yeast telomeres is presumably related to its binding to the exposed G-strand (1-3, 5). Cdc13-1p (P371S), a temperature-sensitive mutant form of Cdc13p, is unable to protect telomeres at the restrictive temperature (1). At the non-permissive temperature, cells with the cdc13-1 allele exhibit extensive degradation of telomeres from the 5Ј-ends, the C-rich strands (C-strands). The C-strand degradation results in long single-stranded Gtails (up to 20 kb) at the 3Ј-ends. The abnormal telomeres in cdc13-1 at the non-permissive temperature lead to RAD9-dependent cell cycle arrest at the G 2 /M phase, as well as cell death (1, 6). However, the mechanism of cell death triggered by Cdc13p inactivation is unclear. It was assumed that essential gene deletion because of the C-strand degradation is the cause of the cell death.Yeast apoptosis is not well understood. Bax, Bcl-2, and other established apoptotic proteins have not been found in yeast cells. However, expression of human BAX in yeast induces cell death (7,8), accompanied by mitochondrial alkalinization and cytosol acidification (9). This process can be blocked by coexpression of human anti-apoptosis protein Bcl-2 (8). Additionally, aged mother cells and H 2 O 2 -treated cells have shown apoptosis markers in yeast, including flipping of phosphatidylserine (PS) 1 from the inner leaflet to the outer leaflet of the cytoplasmic membrane, DNA damage (by TUNEL assay), and reactive oxygen species (ROS) induction (10, 11). More recently, a caspase-like protease Yca1p has been identified in yeast and was found to regulate yeast cell death induced by H 2 O 2 treatment (12). Moreover, a bro...

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Section: Mec1 Plays An Important Role In Mediating Apoptoticsupporting

confidence: 86%

Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast

Qi¹,

Li²,

Kuo³

et al. 2003

Journal of Biological Chemistry

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“…In yeasts and plants, homologs of CST appear to ensure telomere stability by capping chromosome ends [3,[11][12][13][14][15][16][17][18][19][20][21][22]. In vertebrates, the capping function is achieved by shelterin proteins.…”

Section: Discussionmentioning

confidence: 99%

“…In yeasts and plants, homologs of CST are critical for ensuring telomere stability [3,[11][12][13][14][15][16][17][18][19][20][21][22]. In budding yeast, the Cdc13/Stn1/Ten1 complex associates exclusively with the G-overhang and plays important roles in restricting excessive C-strand resection from telomere ends, mediating C-strand fill-in, and regulating telomerase activity [14][15][16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

2012

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Telomere maintenance is critical for genome stability. The newly-identified Ctc1/Stn1/Ten1 complex is important for telomere maintenance, though its precise role is unclear. We report here that depletion of hStn1 induces catastrophic telomere shortening, DNA damage response, and early senescence in human somatic cells. These phenotypes are likely due to the essential role of hStn1 in promoting efficient replication of lagging-strand telomeric DNA. Downregulation of hStn1 accumulates single-stranded G-rich DNA specifically at lagging-strand telomeres, increases telomere fragility, hinders telomere DNA synthesis, as well as delays and compromises telomeric C-strand synthesis. We further show that hStn1 deficiency leads to persistent and elevated association of DNA polymerase α (polα) to telomeres, suggesting that hStn1 may modulate the DNA synthesis activity of polα rather than controlling the loading of polα to telomeres. Additionally, our data suggest that hStn1 is unlikely to be part of the telomere capping complex. We propose that the hStn1 assists DNA polymerases to efficiently duplicate lagging-strand telomeres in order to achieve complete synthesis of telomeric DNA, therefore preventing rapid telomere loss.

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“…In contrast, deletion of EST1 and EST3 (two regulatory subunits of the telomerase complex), although causing telomere loss, failed to elicit the same accumulation in G-strand overhangs. Notably, the overhang increase is reminiscent of the phenotypes of Saccharomyces cerevisiae mutants suffering from dysfunction of telomere binding proteins such as Cdc13p, Ku70, and Ku80 (14)(15)(16)(17). Analysis of such mutants indicated that loss of telomere protection engenders preferential degradation of the telomere C-strand, leading to G-strand overhang accumulation (18)(19)(20).…”

mentioning

confidence: 99%

Telomerase core components protect Candida telomeres from aberrant overhang accumulation

Hsu

McEachern

Dandjinou

et al. 2007

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

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Telomerase is a cellular reverse transcriptase that extends one strand (the G-strand) of the telomere terminal repeats. Aside from this role in telomere length maintenance, telomerase has been proposed to serve a protective function at chromosome ends, although this is not well understood mechanistically. Earlier analysis suggests that, in the pathogenic yeast Candida albicans, the catalytic reverse transcriptase subunit of telomerase (TERT/EST2) can protect telomeres against nucleolytic degradation. In this report we demonstrate that the RNA component (TER1) has a similar function; in addition to complete loss of telomerase activity and progressive telomere attrition, the ter1-⌬⌬ strains manifested a dramatic increase in the amount of G-strand overhangs, consistent with aberrant degradation of the complementary C-strand. We also demonstrate that a catalytically incompetent EST2 protein can suppress such overhang accumulation in the est2-⌬⌬ mutant to the same extent as the wild-type protein. Altogether, our data support the notion that the Candida telomerase core components mediate a protective function through a mechanism that is independent of its catalytic activity.G-strand ͉ telomerase RNA ͉ telomerase reverse transcriptase

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Cdc13 prevents telomere uncapping and Rad50-dependent homologous recombination

Cited by 80 publications

References 47 publications

Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast

Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

Telomerase core components protect Candida telomeres from aberrant overhang accumulation

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