Abstract
Manganese is an essential trace element, whose intracellular levels need to be carefully regulated. Mn(2+) acts as a cofactor for many enzymes and excess of Mn(2+) is toxic. Alterations in Mn(2+) homeostasis affect metabolic functions and mutations in the human Mn(2+)/Ca(2+) transporter ATP2C1 have been linked to Hailey-Hailey disease. By deletion of the yeast orthologue PMR1 we have studied the impact of Mn(2+) on cell cycle progression and show that an excess of cytosolic Mn(2+) 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 Mn(2+) pool requires a functional morphology checkpoint to avoid the formation of polyploid cells.
Highlights
The P-type ATPase Pmr1 provides a major route for cellular detoxification of manganese
Excess of Cytosolic Mn2ϩ Impairs DNA Synthesis and S-phase Progression—Pmr1 is a key regulator of the intracellular Mn2ϩ levels, offering the possibility to investigate the impact of impaired Mn2ϩ homeostasis on cell cycle progression
Addition of extracellular MnCl2 (Fig. 1, A, ϩMnCl2) exacerbated this delay in pmr1⌬ cells (S-phase peaked after 80 min) but did not affect wild type (WT) cells (S-phase peaked after 40 min), whereas the addition of extracellular CaCl2 did not affect S-phase progression indicating a Mn2ϩ-dependent delay
Summary
The P-type ATPase Pmr provides a major route for cellular detoxification of manganese. Correct ion homeostasis is essential for the control of biochemical processes in eukaryotic cells This is the case of the trace element Mn2ϩ that is required as a cofactor for a wide range of enzymes located in every cellular compartment [1, 2]. Mn2؉ Homeostasis and Cell Cycle Regulation the budding cycle is maintained by the presence of a checkpoint that blocks Swe degradation, delaying mitosis in response to defects in growth or bud formation. Our results clearly demonstrate that Pmr is needed to buffer alterations in Mn2ϩ levels, which would otherwise cause loss of cell cycle control, genetic instability, and multinucleation, primary events in tumor formation in higher eukaryotic cells
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