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The length of the shortest telomere as the major determinant of the onset of replicative senescence.

TitleThe length of the shortest telomere as the major determinant of the onset of replicative senescence.
Publication TypeJournal Article
Year of Publication2013
AuthorsXu, Z, Duc, KDao, Holcman, D, Teixeira, MTeresa
JournalGenetics
Volume194
Issue4
Pagination847-57
Date Published2013 Aug
ISSN1943-2631
KeywordsMeiosis, Mitosis, Models, Genetic, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Stochastic Processes, Telomere, Telomere Homeostasis, Telomere Shortening
Abstract

The absence of telomerase in many eukaryotes leads to the gradual shortening of telomeres, causing replicative senescence. In humans, this proliferation barrier constitutes a tumor suppressor mechanism and may be involved in cellular aging. Yet the heterogeneity of the senescence phenotype has hindered the understanding of its onset. Here we investigated the regulation of telomere length and its control of senescence heterogeneity. Because the length of the shortest telomeres can potentially regulate cell fate, we focus on their dynamics in Saccharomyces cerevisiae. We developed a stochastic model of telomere dynamics built on the protein-counting model, where an increasing number of protein-bound telomeric repeats shift telomeres into a nonextendable state by telomerase. Using numerical simulations, we found that the length of the shortest telomere is well separated from the length of the others, suggesting a prominent role in triggering senescence. We evaluated this possibility using classical genetic analyses of tetrads, combined with a quantitative and sensitive assay for senescence. In contrast to mitosis of telomerase-negative cells, which produces two cells with identical senescence onset, meiosis is able to segregate a determinant of senescence onset among the telomerase-negative spores. The frequency of such segregation is in accordance with this determinant being the length of the shortest telomere. Taken together, our results substantiate the length of the shortest telomere as being the key genetic marker determining senescence onset in S. cerevisiae.

DOI10.1534/genetics.113.152322
Alternate JournalGenetics
PubMed ID23733785
PubMed Central IDPMC3730915
Grant List260906 / / European Research Council / International