Organization and maintenance of the mitochondrial and nuclear genomes are vastly different, yet I have shown that a single serine in the H2A C-terminal tail (H2A-S122) is critical for stability of both genomes in the budding yeast, Saccharomyces cerevisiae. Phosphorylation of H2A-S 122 has previously been implicated in the spindle assembly checkpoint (SAC), however I show that by mutating the serine to an alanine (H2A-S122A), the resulting aneuploidy occurs at a much higher rate than is observed by deleting its immediate downstream kinase BUB1. Furthermore, the H2A-S122A mutant displays an increased susceptibility to DNA damaging agents that is not observed in bubΔ1 deletion cells. Our studies also implicate H2A-S122 as critical to the maintenance of the mitochondrial genome, as upon introduction of the H2A-S122A mutation, cells rapidly lose their mitochondrial genomes.