A two-step model for senescence triggered by a single critically short telomere

TY - JOUR

T1 - A two-step model for senescence triggered by a single critically short telomere

AU - Abdallah, Pauline

AU - Luciano, Pierre

AU - Runge, Kurt W

AU - Lisby, Michael

AU - Géli, Vincent

AU - Gilson, Eric

AU - Teixeira, M Teresa

N1 - Keywords: Cell Cycle; Cell Division; DNA Nucleotidyltransferases; Intracellular Signaling Peptides and Proteins; Models, Biological; Mutation; Protein Binding; Protein-Serine-Threonine Kinases; Rad52 DNA Repair and Recombination Protein; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Spores, Fungal; Telomerase; Telomere

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1038/ncb1911

DO - 10.1038/ncb1911

M3 - Journal article

C2 - 19597486

SN - 1465-7392

VL - 11

SP - 988

EP - 993

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -