Impaired Manganese Metabolism Causes Mitotic Misregulation

Manganese is an essential trace element, whose intracellular levels need to be carefully regulated. Mn2+ acts as a cofactor for many enzymes and excess of Mn2+ is toxic. Alterations in Mn2+ homeostasis affect metabolic functions and mutations in the human Mn2+/Ca2+ transporter ATP2C1 have been linked to Hailey-Hailey disease. By deletion of the yeast orthologue PMR1 we have studied the impact of Mn2+ on cell cycle progression and show that an excess of cytosolic Mn2+ alters S-phase transit, induces transcriptional up-regulation of cell cycle regulators, bypasses the need for S-phase cell cycle checkpoints and predisposes to genomic instability. On the other hand, we find that depletion of the Golgi Mn2+ pool requires a functional morphology checkpoint to avoid the formation of polyploid cells. The P-type ATPase Pmr1 provides a major route for cellular detoxification of manganese. Disregulation of Mn2+ homeostasis impairs genome replication and cell cycle progression. Genome instability and endomitosis can be triggered by alterations in cytosolic or Golgi Mn2+ levels. The Mn2+-dependent cell cycle defects might explain disease phenotypes observed in Hailey-Hailey patients having mutations in the human PMR1 orthologue ATP2C1.