Tdp1 protects against oxidative DNA damage in non-dividing fission yeast.
In humans, a mutation in the tyrosyl-DNA phosphodiesterase (Tdp1) is responsible for the recessively inherited syndrome spinocerebellar ataxia with axonal neuropathy (SCAN1). Tdp1 is a well-conserved DNA repair enzyme, which processes modified 3' phospho-DNA adducts in vitro. Here, we report that in the yeast Schizosaccharomyces pombe, tdp1 mutant cells progressively accumulate DNA damage and rapidly lose viability in a physiological G0/quiescent state. Remarkably, this effect is independent of topoisomerase I function. Moreover, we provide evidence that Tdp1, with the polynucleotide kinase (Pnk1), processes the same naturally occurring 3'-ends, produced from oxidative DNA damage in G0. We also found that one half of the dead cells lose their nuclear DNA. Nuclear DNA degradation is genetically programmed and mainly depends on the two DNA damage checkpoint responses, ATM/Tel1 and ATR/Rad3, reminiscent to programmed cell death. Diminishing the respiration rate or treating cells with a low concentration of antioxidants rescues the quiescent tdp1 mutant cells. These findings suggest that mitochondrial respiration causes neuronal cell death in the SCAN1 syndrome and in other neurological disorders.
Ben Hassine
Samia
S
Dynamic of the Genome Unit, Genomes and Genetic Department, Institut Pasteur, URA2171, Paris, France.
Arcangioli
Benoit
B
D017209:Apoptosis; D002455:Cell Division; D002467:Cell Nucleus / Q000201:enzymology; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D004260:DNA Repair; D050296:Microbial Viability; D008928:Mitochondria / Q000201:enzymology; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011116:Polynucleotide 5'-Hydroxyl-Kinase / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D012568:Schizosaccharomyces / Q000166:cytology* / Q000201:enzymology*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*
D017382:Reactive Oxygen Species; D029702:Schizosaccharomyces pombe Proteins; C539712:Tdp1 protein, S pombe; C448179:PnK1 protein, S pombe; D011116:Polynucleotide 5'-Hydroxyl-Kinase; D010727:Phosphoric Diester Hydrolases; C122147:tyrosyl-DNA phosphodiesterase