title: DNA damage checkpoint adaptation genes are required for division of cells harbouring eroded telomeres.
abstract: In budding yeast, telomerase and the Cdc13p protein are two key players acting to ensure telomere stability. In the absence of telomerase, cells eventually enter a growth arrest which only few can overcome via a conserved process; such cells are called survivors. Survivors rely on homologous recombination-dependent mechanisms for telomeric repeat addition. Previously, we showed that such survivor cells also manage to bypass the loss of the essential Cdc13p protein to give rise to Cdc13-independent (or cap-independent) strains. Here we show that Cdc13-independent cells grow with persistently recognized DNA damage, which does not however result in a checkpoint activation; thus no defect in cell cycle progression is detectable. The absence of checkpoint signalling rather is due to the accumulation of mutations in checkpoint genes such asRAD24orMEC1. Importantly, our results also show that cells that have lost the ability to adapt to persistent DNA damage, also are very much impaired in generating cap-independent cells. Altogether, these results show that while the capping process can be flexible, it takes a very specific genetic setup to allow a change from canonical capping to alternative capping. We hypothesize that in the alternative capping mode, genome integrity mechanisms are abrogated, which could cause increased mutation frequencies. These results from yeast have clear parallels in transformed human cancer cells and offer deeper insights into processes operating in pre-cancerous human cells that harbour eroded telomeres.
authors.affiliation: Dept of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, Rue Jean Mignault, Sherbrooke, J1E 4K8, Canada.
authors.forename: Sofiane Y
authors.initials: SY
authors.lastname: Mersaoui
authors.affiliation: Dept of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, Rue Jean Mignault, Sherbrooke, J1E 4K8, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Gravel
authors.affiliation: Dept of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, Rue Jean Mignault, Sherbrooke, J1E 4K8, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Karpov
authors.affiliation: Dept of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201, Rue Jean Mignault, Sherbrooke, J1E 4K8, Canada.
authors.forename: Raymund J
authors.initials: RJ
authors.lastname: Wellinger
keywords: DNA damage checkpoints; chromosome capping; telomeres