Abstract
Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here, we show that telomerase-deficient cells bearing a single, very short telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence. We further show that Mec1p-ATR specifically recognizes the single, very short telomere causing the accelerated senescence. Strikingly, before entering senescence, cells divide for several generations despite complete erosion of their shortened telomeres. This pre-senescence growth requires RAD52 (radiation sensitive) and MMS1 (methyl methane sulfonate sensitive), and there is no evidence for major inter-telomeric recombination. We propose that, in the absence of telomerase, a very short telomere is first maintained in a pre-signalling state by a RAD52-MMS1-dependent pathway and then switches to a signalling state leading to senescence through a Mec1p-dependent checkpoint.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle / genetics
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Cell Cycle / physiology
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Cell Division / genetics
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Cell Division / physiology
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DNA Nucleotidyltransferases / genetics
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DNA Nucleotidyltransferases / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Models, Biological*
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Mutation
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Rad52 DNA Repair and Recombination Protein / genetics
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Rad52 DNA Repair and Recombination Protein / metabolism
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Saccharomyces cerevisiae / cytology
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Saccharomyces cerevisiae / genetics*
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Saccharomyces cerevisiae / physiology
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Saccharomyces cerevisiae Proteins / genetics*
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Saccharomyces cerevisiae Proteins / metabolism
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Signal Transduction / genetics
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Signal Transduction / physiology
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Spores, Fungal / genetics
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Spores, Fungal / physiology
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Telomerase / genetics
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Telomerase / metabolism
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Telomere / genetics*
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Telomere / metabolism
Substances
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Intracellular Signaling Peptides and Proteins
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Mms1 protein, S cerevisiae
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RAD52 protein, S cerevisiae
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Rad52 DNA Repair and Recombination Protein
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Saccharomyces cerevisiae Proteins
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MEC1 protein, S cerevisiae
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Protein Serine-Threonine Kinases
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TEL1 protein, S cerevisiae
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DNA Nucleotidyltransferases
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FLP recombinase
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Telomerase