A unified alternative telomere-lengthening pathway in yeast survivor cells

Kockler, Zachary; Comeron, Josep M.; Malkova, Anna

doi:10.1016/j.molcel.2021.02.004

Cited by 38 publications

(33 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Subsequent partial digestion experiment (panel C) indicated that telomeres in pptr plants were formed by tandemly arranged units composed of telomeric (TTTAGGG) n repeats and an adjacent DNA sequence harbouring a single Mse I site. Thus, the structure of telomeres in pptr survivors is similar to that observed in ALT yeast survivors of the type I ( 63 ) or its subsequent unified form with type II survivors (as recently described by ( 64 )). It is plausible that P. patens ALT survivors benefit (similarly to yeasts) from the high efficiency of homologous recombination in this organism.…”

Section: Discussionsupporting

confidence: 80%

Evolution of plant telomerase RNAs: farther to the past, deeper to the roots

Fajkus

Kilar

Nelson

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

The enormous sequence heterogeneity of telomerase RNA (TR) subunits has thus far complicated their characterization in a wider phylogenetic range. Our recent finding that land plant TRs are, similarly to known ciliate TRs, transcribed by RNA polymerase III and under the control of the type-3 promoter, allowed us to design a novel strategy to characterize TRs in early diverging Viridiplantae taxa, as well as in ciliates and other Diaphoretickes lineages. Starting with the characterization of the upstream sequence element of the type 3 promoter that is conserved in a number of small nuclear RNAs, and the expected minimum TR template region as search features, we identified candidate TRs in selected Diaphoretickes genomes. Homologous TRs were then used to build covariance models to identify TRs in more distant species. Transcripts of the identified TRs were confirmed by transcriptomic data, RT-PCR and Northern hybridization. A templating role for one of our candidates was validated in Physcomitrium patens. Analysis of secondary structure demonstrated a deep conservation of motifs (pseudoknot and template boundary element) observed in all published TRs. These results elucidate the evolution of the earliest eukaryotic TRs, linking the common origin of TRs across Diaphoretickes, and underlying evolutionary transitions in telomere repeats.

show abstract

Section: Discussionsupporting

confidence: 80%

Evolution of plant telomerase RNAs: farther to the past, deeper to the roots

Fajkus

Kilar

Nelson

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…To model the appearance of non-terminal first arrests with generations after telomerase inactivation, we used a telomere-shortening model we previously built, in which the shortest telomere deterministically triggers the checkpoint arrest at a threshold length. The threshold that best fitted the experimental data is 61 bp, close to the 75 bp “recombination length” proposed in a recent work to promote activation of resection and initiate Rad51-dependent break-induced replication to elongate telomeres [ 24 ]. However, this deterministic model does not capture the heterogeneity of the distribution of the appearance of the non-terminal arrests (Additional file 1 : Fig.…”

Section: Discussionsupporting

confidence: 71%

Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae

et al. 2021

View full text Add to dashboard Cite

Background Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known. Results Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states. Conclusions Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.

show abstract

“…To model the appearance of non-terminal first arrests with generations after telomerase inactivation, we used a telomere-shortening model we previously built, in which the shortest telomere deterministically triggers the checkpoint arrest at a threshold length. The threshold that best fitted the experimental data is 61 bp, close to the 75 bp "recombination length" proposed in a recent work to promote activation of resection and initiate Rad51-dependent break-induced replication to elongate telomeres (24). However, this deterministic model does not capture the heterogeneity of the distribution of the appearance of the non-terminal arrests (Fig.…”

Section: Discussionsupporting

confidence: 58%

Telomere shortening causes distinct cell division regimes during replicative senescence inSaccharomyces cerevisiae

Martin¹,

Doumic

Teixeira

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known. Results: Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states. Conclusions: Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.

show abstract

A unified alternative telomere-lengthening pathway in yeast survivor cells

Cited by 38 publications

References 50 publications

Evolution of plant telomerase RNAs: farther to the past, deeper to the roots

Evolution of plant telomerase RNAs: farther to the past, deeper to the roots

Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae

Telomere shortening causes distinct cell division regimes during replicative senescence inSaccharomyces cerevisiae

Contact Info

Product

Resources

About