Interplay between Nonsense-Mediated mRNA Decay and DNA Damage Response Pathways Reveals that Stn1 and Ten1 Are the Key CST Telomere-Cap Components

Holstein, Eva-Maria; Clark, Kate Rosalind Mary; Lydall, David

doi:10.1016/j.celrep.2014.04.017

Cited by 21 publications

(40 citation statements)

References 54 publications

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“…Competition model fitness rankings of deletions on P15 are similar to the published logistic model rankings from Addinall et al (2011) for the fastest and slowest growing strains ( Figure 10). Both models also agree with rankings from independent spot tests for these strains (Maringele and Lydall, 2002;Zubko et al, 2004;Holstein et al, 2014;Foster et al, 2006). Middle rankings, however, disagree between models, and Spearman's Rho between M DR estimates is just 0.635.…”

Section: Discussionsupporting

confidence: 57%

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Modelling Competition for Nutrients between Microbial Populations Growing on a Solid Agar Surface

Daniel

Lawless

2017

Preprint

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Motivation: Growth rate is a major component of the evolutionary fitness of microbial organisms and an excellent surrogate for cell health. In the high-throughput procedures QFA and SGA, microbial cultures are inoculated in an array on solid agar, and growth is measured to obtain quantitative fitness estimates. Neighbouring cultures, which are often different genetic strains, consume nutrients at different rates, creating gradients in nutrient density. We believe that diffusion of nutrients between cultures is affecting growth in these experiments. Current analysis does not account for this; instead, it is assumed that cultures grow independently. I use a network model of nutrient diffusion and nutrient-dependent growth, to correct for competition, to try to improve the accuracy and precision of fitness estimates. I test the model against QFA data from studies on telomere function in Saccharomyces cerevisiae. Ultimately, the model might be used to improve the reliability of screens for genetic interaction and drug sensitivity. Results: I fit the competition model to a QFA plate from Addinall et al. (2011). Using far fewer parameters (387 vs 1152), the new model fits timecourses with similar closeness to the previous model. Fitness estimates are less precise for the fastest growing strains, but more precise for the majority of strains (36 out of 50). Fitness rankings agree in the positions of the fastest and slowest growing strains, but disagree in the middle positions. In a cross-plate validation experiment, the competition model overestimates timecourses to a similar degree that the previous model underestimates. A different method of fitting is required to find globally optimal solutions which might improve reliability. Availability and Implementation: CANS, a Python package developed for the analysis in this paper, is freely available at https://github.com/lwlss/CANS.

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Section: Discussionsupporting

confidence: 57%

“…Repeats of each strain increase statistical power. Furthermore, for several strains, independent spot tests have been published and may be used for validation (Maringele and Lydall, 2002;Zubko et al, 2004;Holstein et al, 2014;Foster et al, 2006).…”

Section: The P15 Datasetmentioning

confidence: 99%

Modelling Competition for Nutrients between Microbial Populations Growing on a Solid Agar Surface

Daniel

Lawless

2017

Preprint

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“…For example, yeast Stn1 inhibits telomerase binding to Cdc13 (Chandra et al, 2001), arguing that CST components must be modified in some fashion for replication, perhaps via phosphorylation of Cdc13 (Li et al, 2009) and Stn1 (Liu et al, 2014). In some genetic backgrounds, STN1 and TEN1 stabilize chromosome ends in a Cdc13-independent manner (Holstein et al, 2014;Petreaca et al, 2006). Moreover, relative to human cells deficient in STN1 or CTC1, cells lacking TEN1 exhibit more severe growth defects, a higher frequency of chromosomes lacking telomeric DNA, and more anaphase bridges (Kasbek et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Dynamic Interactions of Arabidopsis TEN1: Stabilizing Telomeres in Response to Heat Stress

et al. 2016

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Telomeres are the essential nucleoprotein structures that provide a physical cap for the ends of linear chromosomes. The highly conserved CST (CTC1/STN1/TEN1) protein complex facilitates telomeric DNA replication and promotes telomere stability. Here we report three unexpected properties of Arabidopsis thaliana TEN1 that indicate it possesses functions distinct from other previously characterized telomere proteins. First, we show that telomeres in ten1 mutants are highly sensitive to thermal stress. Heat shock causes abrupt and dramatic loss of telomeric DNA in ten1 plants, likely via deletional recombination. Second, we show that AtTEN1 has the properties of a heat-shock induced molecular chaperone. At elevated temperature, AtTEN1 rapidly assembles into high molecular weight homo-oligomeric complexes that efficiently suppress heat-induced aggregation of model protein substrates in vitro. Finally, we report that AtTEN1 specifically protects CTC1 from heat-induced aggregation in vitro, and from heat-induced protein degradation and loss of telomere association in vivo. Collectively, these observations define Arabidopsis TEN1 as a highly dynamic protein that works in concert with CTC1 to preserve telomere integrity in response to environmental stress.

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“…rif1∆, made cells considerably sicker in the rad9∆ cdc13-1 (UD) context. Conversely, the nmd∆ mutations improved rad9∆ cdc13-1 (UD) fitness more than cdc13-1 (UD) fitness, suggesting that NMD has stronger effects on ssDNA accumulation in the absence or Rad9 (Holstein et al, 2014). It was notable that mutations affecting the checkpoint sliding clamp (ddc1∆, rad24∆ and rad17∆) clustered very tightly in Figure 3B.…”

Section: Acute Exposure To Telomere Defectsmentioning

confidence: 98%

“…cdc13-1 strains are comparatively viable in small scale up-down assays and the effect of nmd2∆ correlates with lower levels of ssDNA production at defective telomeres in nmd2∆ mutants (Holstein et al, 2014).…”

Section: Effects Of Different Gene Deletions Across Several Telomere mentioning

confidence: 99%

Systematic analysis of the effects of the DNA damage response network in telomere defective budding yeast

Holstein¹,

Ngo

Lawless³

et al. 2017

Preprint

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Functional telomeres are critically important to eukaryotic genetic stability. Budding yeast is a powerful model organism for genetic analysis and yeast telomeres are maintained by very similar mechanisms to human telomeres. Scores of proteins and pathways are known to affect telomere function. Here, we report a series of related genome-wide genetic interaction screens performed on budding yeast cells with acute or chronic telomere defects. We examined genetic interactions in cells defective in Cdc13 and Stn1, affecting two components of CST, a single stranded DNA (ssDNA) binding complex that binds telomeric DNA. We investigated genetic interactions in cells with defects in Rfa3, affecting the major ssDNA binding protein, RPA, which has overlapping functions with CST at telomeres. We also examined genetic interactions in cells lacking EXO1 or RAD9, affecting different aspects of the DNA damage response in a cdc13-1 background. Comparing fitness profiles across the data sets allows us build up a picture of the specific responses to different types of dysfunctional telomeres. Our results show that there is no universal response to telomere defects. To help others engage with the large volumes of data we make the data available via two interactive web-based tools: Profilyzer and DIXY. Among numerous genetic interactions we found the chk1∆ mutation improved fitness of cdc13-1 exo1∆ cells more than other checkpoint mutations (ddc1∆, rad9∆, rad17∆, rad24∆), whereas in cdc13-1 cells the effects of all checkpoint mutations were similar. We find that Chk1 stimulates resection at defective telomeres, revealing a new role for Chk1 in the eukaryotic DNA damage response network.

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Interplay between Nonsense-Mediated mRNA Decay and DNA Damage Response Pathways Reveals that Stn1 and Ten1 Are the Key CST Telomere-Cap Components

Cited by 21 publications

References 54 publications

Modelling Competition for Nutrients between Microbial Populations Growing on a Solid Agar Surface

Modelling Competition for Nutrients between Microbial Populations Growing on a Solid Agar Surface

Dynamic Interactions of Arabidopsis TEN1: Stabilizing Telomeres in Response to Heat Stress

Systematic analysis of the effects of the DNA damage response network in telomere defective budding yeast

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