Impaired coenzyme A synthesis in fission yeast causes defective mitosis, quiescence-exit failure, histone hypoacetylation and fragile DNA

Abstract

Biosynthesis of coenzyme A (CoA) requires a five-step process using pantothenate and cysteine in the fission yeastSchizosaccharomyces pombe. CoA contains a thiol (SH) group, which reacts with carboxylic acid to form thioesters, giving rise to acyl-activated CoAs such as acetyl-CoA. Acetyl-CoA is essential for energy metabolism and protein acetylation, and, in higher eukaryotes, for the production of neurotransmitters. We isolated a novelS. pombetemperature-sensitive strainppc1-537mutated in the catalytic region of phosphopantothenoylcysteine synthetase (designated Ppc1), which is essential for CoA synthesis. The mutant becomes auxotrophic to pantothenate at permissive temperature, displaying greatly decreased levels of CoA, acetyl-CoA and histone acetylation. Moreover,ppc1-537mutant cells failed to restore proliferation from quiescence. Ppc1 is thus the product of a super-housekeeping gene. Theppc1-537mutant showed combined synthetic lethal defects with five of six histone deacetylase mutants, whereassir2deletion exceptionally rescued theppc1-537phenotype. In synchronous cultures,ppc1-537cells can proceed to the S phase, but lose viability during mitosis failing in sister centromere/kinetochore segregation and nuclear division. Additionally, double-strand break repair is defective in theppc1-537mutant, producing fragile broken DNA, probably owing to diminished histone acetylation. The CoA-supported metabolism thus controls the state of chromosome DNA.