title: Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Enerlyn M
authors.initials: EM
authors.lastname: Lozada
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.|Current affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Andrysik
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Moying
authors.initials: M
authors.lastname: Yin
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Redilla
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Rice
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D063209:N-Terminal Acetyltransferase A / Q000378:metabolism*; D063213:N-Terminal Acetyltransferase E / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D054875:Ubiquitination; D020687:cdc25 Phosphatases / Q000378:metabolism*
chemical_list: D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; C462506:HDAC11 protein, human; D006655:Histone Deacetylases
keywords: ARD1; Cdc25A acetylation; DNA damage; HDAC11; cancer