Novel CDK-independent function of CDC25 phosphatases in mRNA translation

Molecular and functional networks driving coordination between cell cycle and mRNA translation remain to be explored. Here, we use mass spectrometry-based proteomics to comprehensively investigate the interactome and phosphoproteome of the cell cycle regulator CDC25A. We identify actors of mRNA regulation, such as RNA-binding proteins and translation factors, as interacting partners of CDC25A. CDC25A overexpression increases global translation, whereas catalytic inactivation or pharmacological inhibition decreases protein synthesis. A Cyclin-Dependent Kinase (CDK) interaction-deficient mutant of CDC25A also enhances translation, indicating a CDK-independent role. Our results further reveal an interplay between CDC25A and CDC25B whereby downregulation of CDC25A leads to compensatory overexpression of CDC25B. The roles of CDC25A and CDC25B in mRNA translation are independent of their roles in the cell cycle, with CDC25A possibly regulating translation elongation and CDC25B rather involved in initiation. In acute myeloid leukemia cells, CDC25A depletion also inhibits translation, suggesting its potential relevance as a therapeutic target. We propose that CDC25 phosphatases might be signaling platforms coordinating cell cycle progression with protein synthesis.