Cdc13 Telomere Capping Decreases Mec1 Association but Does Not Affect Tel1 Association with DNA Ends

Hirano, Yukinori; Sugimoto, Katsunori

doi:10.1091/mbc.e06-12-1074

Cited by 47 publications

(58 citation statements)

References 66 publications

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“…In S. cerevisiae, the mitosis entry checkpoint1 (Mec1) kinase, the ATR homolog, has a predominant role in response to DSBs. In agreement with this, S. cerevisiae cells deficient in telomerase or the ssDNA binding protein Cdc13 activate a Mec1-dependent checkpoint (Enomoto et al, 2002;IJpma and Greider, 2003;Hirano and Sugimoto, 2007).…”

Section: Introductionsupporting

confidence: 56%

ArabidopsisATM and ATR Kinases Prevent Propagation of Genome Damage Caused by Telomere Dysfunction

et al. 2011

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The ends of linear eukaryotic chromosomes are hidden in nucleoprotein structures called telomeres, and loss of the telomere structure causes inappropriate repair, leading to severe karyotypic and genomic instability. Although it has been shown that DNA damaging agents activate a DNA damage response (DDR), little is known about the signaling of dysfunctional plant telomeres. We show that absence of telomerase in Arabidopsis thaliana elicits an ATAXIA-TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR)-dependent DDR at telomeres, principally through ATM. By contrast, telomere dysfunction induces an ATR-dependent response in telomeric Conserved telomere maintenance component1 (Ctc1)-Suppressor of cdc thirteen (Stn1)-Telomeric pathways in association with Stn1 (CST)-complex mutants. These results uncover a new role for the CST complex in repressing the ATR-dependent DDR pathway in plant cells and show that plant cells use two different DNA damage surveillance pathways to signal telomere dysfunction. The absence of either ATM or ATR in ctc1 and stn1 mutants significantly enhances developmental and genome instability while reducing stem cell death. These data thus give a clear illustration of the action of ATM/ATR-dependent programmed cell death in maintaining genomic integrity through elimination of genetically unstable cells.

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Section: Introductionsupporting

confidence: 56%

ArabidopsisATM and ATR Kinases Prevent Propagation of Genome Damage Caused by Telomere Dysfunction

et al. 2011

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“…DNA double-strand breaks are typically resected, initially being degraded from 59 to 39 to create single-stranded 39 overhangs at the break (White and Haber 1990). However, it has been shown that when short tracts of telomere repeat sequences are placed adjacent to the DNA break site, the broken DNA end is protected from degradation (Diede and Gottschling 1999;Michelson et al 2005;Hirano and Sugimoto 2007). The presence of this telomere ''seed'' sequence also greatly stimulates the addition of new telomere repeats to the DSB (Diede and Gottschling 1999).…”

Section: Resultsmentioning

confidence: 99%

“…The presence of this telomere ''seed'' sequence also greatly stimulates the addition of new telomere repeats to the DSB (Diede and Gottschling 1999). The ability of this de novo telomere to cap the new DNA end has been shown to be critically dependent upon Cdc13 (Diede and Gottschling 1999;Hirano and Sugimoto 2007). Since Cdc13 is proficient for telomere localization in ten1-ts strains and the mutant Ten1 RAD52 ten1D 47 6 24 2.1 6 0.8 1.0 6 0.6 1.2 6 1.0 0.6 6 0.6 rad52D ten1D 40 6 15 0.5 6 0.5 0.2 6 0.3 0.2 6 0.1 0.4 6 0.6 exo1D ten1D…”

Section: Resultsmentioning

confidence: 99%

TEN1Is Essential forCDC13-Mediated Telomere Capping

Petreaca

Gasparyan

et al. 2009

Genetics

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Telomere binding proteins protect chromosome ends from degradation and mask chromosome termini from checkpoint surveillance. In Saccharomyces cerevisiae, Cdc13 binds single-stranded G-rich telomere repeats, maintaining telomere integrity and length. Two additional proteins, Ten1 and Stn1, interact with Cdc13 but their contributions to telomere integrity are not well defined. Ten1 is known to prevent accumulation of aberrant single-stranded telomere DNA; whether this results from defective end protection or defective telomere replication is unclear. Here we report our analysis of a new group of ten1 temperature-sensitive (ts) mutants. At permissive temperatures, ten1-ts strains display greatly elongated telomeres. After shift to nonpermissive conditions, however, ten1-ts mutants accumulate extensive telomeric single-stranded DNA. Cdk1 activity is required to generate these single-stranded regions, and deleting the EXO1 nuclease partially suppresses ten1-ts growth defects. This is similar to cdc13-1 mutants, suggesting ten1-ts strains are defective for end protection. Moreover, like Cdc13, our analysis reveals Ten1 promotes de novo telomere addition. Interestingly, in ten1-ts strains at high temperatures, telomeric singlestranded DNA and Rad52-YFP repair foci are strongly induced despite Cdc13 remaining associated with telomeres, revealing Cdc13 telomere binding is not sufficient for end protection. Finally, unlike cdc13-1 mutants, ten1-ts strains display strong synthetic interactions with mutations in the POLa complex. These results emphasize that Cdc13 relies on Ten1 to execute its essential function, but leave open the possibility that Ten1 has a Cdc13-independent role in DNA replication.

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“…Because the telomere-binding proteins Cdc13 and Rap1 stimulate de novo telomere addition at artificial sequences in S. cerevisiae (12)(13)(14)(15)43), we hypothesized that one or both of these proteins could be responsible for the enhancing activity of the Stim sequence. Although Cdc13 and Rap1 bind similar sequences, we were able to design artificial sequences that bind with great preference to one protein as measured in vitro.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Hot Spots of De Novo Telomere Addition in the Yeast Genome Contain Proximal Enhancers That Bind Cdc13

Obodo

Platts

Seloff

et al. 2016

Molecular and Cellular Biology

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DNA double-strand breaks (DSBs) pose a threat to genome stability and are repaired through multiple mechanisms. Rarely, telomerase, the enzyme that maintains telomeres, acts upon a DSB in a mutagenic process termed telomere healing. The probability of telomere addition is increased at specific genomic sequences termed sites of repair-associated telomere addition (SiRTAs). By monitoring repair of an induced DSB, we show that SiRTAs on chromosomes V and IX share a bipartite structure in which a core sequence (Core) is directly targeted by telomerase, while a proximal sequence (Stim) enhances the probability of de novo telomere formation. The Stim and Core sequences are sufficient to confer a high frequency of telomere addition to an ectopic site. Cdc13, a single-stranded DNA binding protein that recruits telomerase to endogenous telomeres, is known to stimulate de novo telomere addition when artificially recruited to an induced DSB. Here we show that the ability of the Stim sequence to enhance de novo telomere addition correlates with its ability to bind Cdc13, indicating that natural sites at which telomere addition occurs at high frequency require binding by Cdc13 to a sequence 20 to 100 bp internal from the site at which telomerase acts to initiate de novo telomere addition. Chromosomes in the budding yeast Saccharomyces cerevisiae, as in all eukaryotes, terminate with specialized nucleoprotein structures called telomeres. S. cerevisiae telomeric DNA consists of ϳ250 to 350 bp of TG 1-3 /AC 1-3 repeats and a short (ϳ10-bp) terminal G-rich 3= overhang (1). Because the conventional DNA replication machinery cannot fully replicate chromosome ends, telomeres shorten with each cell division cycle. In most eukaryotes, telomere shortening is counteracted by the enzyme telomerase, a ribonucleoprotein complex that uses an intrinsic RNA subunit as the template for telomeric DNA synthesis. Associated with telomeric DNA are proteins that protect chromosome ends from nucleolytic resection and prevent chromosome end-to-end fusions by distinguishing natural chromosome ends from ends generated by DNA double-strand breaks (DSBs) (2). These protective functions make telomeres essential for the maintenance of genome integrity and cell viability.In S. cerevisiae, optimal telomere length requires a balance between positive and negative regulatory mechanisms mediated by telomere-binding proteins, including Cdc13 and Rap1 (3). Cdc13, a telomere sequence-specific single-stranded DNA (ssDNA) binding protein, recruits telomerase to telomeres during the S/G 2 phase of the cell cycle through interaction with Est1, a subunit of the telomerase holoenzyme (reviewed in reference 3). Rap1 binds to the double-stranded telomeric repeat, forming a telomere length-regulatory complex through interactions of its C-terminal domain with Rif1 and Rif2 (4,5). Regulation occurs through a counting mechanism in which telomere length is inversely proportional to the number of Rif1 and Rif2 molecules present at a telomere (6, 7).Cells experience insults to t...

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Cdc13 Telomere Capping Decreases Mec1 Association but Does Not Affect Tel1 Association with DNA Ends

Cited by 47 publications

References 66 publications

ArabidopsisATM and ATR Kinases Prevent Propagation of Genome Damage Caused by Telomere Dysfunction

ArabidopsisATM and ATR Kinases Prevent Propagation of Genome Damage Caused by Telomere Dysfunction

TEN1Is Essential forCDC13-Mediated Telomere Capping

Endogenous Hot Spots of De Novo Telomere Addition in the Yeast Genome Contain Proximal Enhancers That Bind Cdc13

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