Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer
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Enerlyn M. Lozada1, Zdenek Andrysik1,2, Moying Yin1, Nicholas Redilla1, Kathryn Rice1, Peter J. Stambrook1
1Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA
2Current affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
Keywords: Cdc25A acetylation, ARD1, HDAC11, DNA damage, cancer
Received: December 22, 2015 Accepted: February 16, 2016 Published: March 07, 2016
The dual specificity phosphatase Cdc25A is a key regulator of the cell cycle that promotes cell cycle progression by dephosphorylating and activating cyclin-dependent kinases. In response to genotoxicants, Cdc25A undergoes posttranslational modifications which contribute to its proteasome-mediated degradation and consequent cell cycle checkpoint arrest. The most thoroughly studied Cdc25A modification is phosphorylation. We now provide the first evidence that Cdc25A can be acetylated and that it directly interacts with the ARD1 acetyltransferase which acetylates Cdc25A both biochemically and in cultured cells. When acetylated, Cdc25A has an extended half-life. We have also identified the class IV histone deacetylase, HDAC11, as a Cdc25A deacetylase. We further show that DNA damage, such as exposure to methyl methanesulfonate (MMS), etoposide or arsenic, increases Cdc25A acetylation. Importantly, this acetylation modulates Cdc25A phosphatase activity and its function as a cell cycle regulator, and may reflect a cellular response to DNA damage. Since Cdc25A, ARD1, and HDAC11 are frequently dysregulated in multiple types of cancer, our findings may provide insight into a novel mechanism in carcinogenesis.
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