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Genes Dev. 2018 Dec 1;32(23-24):1499-1513. doi: 10.1101/gad.318485.118. Epub 2018 Nov 21.

Adaptation to DNA damage checkpoint in senescent telomerase-negative cells promotes genome instability.

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Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, UMR8226, Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Physico-Chimique, Paris Sciences et Lettres (PSL) Research University, Sorbonne Université, F-75005 Paris, France.
Institute of Molecular and Cellular Radiobiology, Commissiriat à l'Énergie Atomique et aux Énergies Alternatives (CEA)/Direction de la Recherche Fondamentale (DRF), 92260 Fontenay-aux-Roses Cedex, France.
U967, Institut National de la Santé et de la Recherche Médicale (INSERM), 92260 Fontenay-aux-Roses Cedex, France.
UMR967, Université Paris-Diderot et Université Paris-Sud, 92260 Fontenay-aux-Roses cedex, France.
Department of Fundamental Microbiology, University of Lausanne, CH-1015 Lausanne, Switzerland.
Department of Developmental Biology and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.
UMR7104, CNRS, 67400 Illkirch, France.
U964, INSERM, 67400 Illkirch, France.
Université de Strasbourg, 67400 Illkirch, France.
Contributed equally


In cells lacking telomerase, telomeres gradually shorten during each cell division to reach a critically short length, permanently activate the DNA damage checkpoint, and trigger replicative senescence. The increase in genome instability that occurs as a consequence may contribute to the early steps of tumorigenesis. However, because of the low frequency of mutations and the heterogeneity of telomere-induced senescence, the timing and mechanisms of genome instability increase remain elusive. Here, to capture early mutation events during replicative senescence, we used a combined microfluidic-based approach and live-cell imaging in yeast. We analyzed DNA damage checkpoint activation in consecutive cell divisions of individual cell lineages in telomerase-negative yeast cells and observed that prolonged checkpoint arrests occurred frequently in telomerase-negative lineages. Cells relied on the adaptation to the DNA damage pathway to bypass the prolonged checkpoint arrests, allowing further cell divisions despite the presence of unrepaired DNA damage. We demonstrate that the adaptation pathway is a major contributor to the genome instability induced during replicative senescence. Therefore, adaptation plays a critical role in shaping the dynamics of genome instability during replicative senescence.


Cdc5; DNA damage checkpoint; adaptation; genomic instability; senescence; telomere

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