Reversible DNA damage checkpoint activation at the presenescent stage in telomerase-deficient cells of Saccharomyces cerevisiae.

Abstract

The telomere protects the ends of eukaryotic linear chromosomes, and its shortening or erosion is recognized as DNA damage, leading to loss of proliferation activity and, thus, cellular senescence at the population level. Here, using a GFP-based DNA damage checkpoint marker suited for single-cell observation of Saccharomyces cerevisiae cells, we correlated the checkpoint status of telomere-shortened cells with their behavior. We show that some cells possessing short telomeres retain proliferation capacity even after the DNA damage checkpoint is activated. At the presenescent stage, the activation of the checkpoint causes cell cycle delay, but does not induce permanent cell cycle arrest, eventually leading to the expansion of cell size that is characteristic of cellular senescence. Moreover, the proliferation capacity of checkpoint-activated cells is not dependent on homologous recombination or the checkpoint adaptation pathway. The retention of proliferation capacity is specific to the telomere-derived DNA damage response, suggesting that damaged telomeres differ functionally from other types of DNA damage. Our data establish the role of the presenescent stage in telomere shortening-induced senescence, which proceeds gradually and is associated with a variety of changes, including altered cell morphology and metabolism.