The telomeres protect chromosome ends from fusion and degradation1. In the absence of a specific telomere elongation mechanism, their DNA progressively shortens with every round of replication leading to replicative senescence2. Here, we show that telomerase-deficient cells bearing a single very short telomere senesce earlier, demonstrating that length of the shortest telomere is a major determinant of the onset of senescence. We further show that Mec1p/ATR recognises specifically the single very short telomere causing the accelerated senescence. Strikingly, before entry into senescence, cells divide for some generations despite a complete erosion of their shortened telomeres. This pre-senescence growth requires RAD52 and MMS1 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.
The ends of linear eukaryotic chromosomes are protected by telomeres, which serve to ensure proper chromosome replication and to prevent spurious recombination at chromosome ends. In this study, we show by single cell analysis that in the absence of telomerase, a single short telomere is sufficient to induce the recruitment of checkpoint and recombination proteins. Notably, a DNA damage response at eroded telomeres starts many generations before senescence and is characterized by the recruitment of Cdc13 (cell division cycle 13), replication protein A, DNA damage checkpoint proteins and the DNA repair protein Rad52 into a single focus. Moreover, we show that eroded telomeres, although remaining at the nuclear periphery, move to the nuclear pore complex. Our results link the DNA damage response at eroded telomeres to changes in subnuclear localization and suggest the existence of collapsed replication forks at eroded telomeres.
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