The dual-specificity phosphatase hYVH1 (DUSP12) is a novel modulator of cellular DNA content

The dual-specificity phosphatase hYVH1 (DUSP12) is an evolutionary conserved phosphatase that also contains a unique zinc binding domain. Recent evidence suggests that this enzyme plays a role in cell survival and ribosome biogenesis. Here we report that hYVH1 expression also affects cell cycle progression. Overexpression of hYVH1 caused a significant increase in polyploidy and in the G(2)/M cell population with a subsequent decrease in the G(0)/G(1) population. Phosphatase activity is dispensable, while the zinc binding domain is necessary and sufficient for hYVH1-mediated cell cycle changes. In agreement with this, siRNA-mediated silencing of hYVH1 expression resulted in a dramatic increase in the G(0)/G(1) population and susceptibility to cellular senescence. Additionally, mass spectrometry-based methods identified novel hYVH1 phosphorylation sites including a C-terminal modification at position Ser(335) in the zinc binding domain. Interestingly, phosphorylation at Ser(335) regulates subcellular targeting of hYVH1 and augments the hYVH1 G(2)/M phenotype. Collectively we demonstrate that hYVH1 is a novel modulator of cell cycle progression; a function mainly mediated by its C-terminal zinc binding domain.