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Updated: Mar 24, 2026
Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
Published on: May 3, 2018
Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with
Enerlyn M Lozada1, Zdenek Andrysik1,2, Moying Yin1
1Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
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.
Insights
The dual specificity phosphatase Cdc25A is acetylated by ARD1 and deacetylated by HDAC11, impacting cell cycle regulation. DNA damage increases Cdc25A acetylation, potentially influencing cancer development.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Oncology
Background:
- Cdc25A is a key cell cycle regulator, promoting progression by activating cyclin-dependent kinases.
- Genotoxic stress induces Cdc25A degradation via posttranslational modifications, leading to cell cycle arrest.
- Phosphorylation is the most studied Cdc25A modification, but acetylation's role is unexplored.
Purpose of the Study:
- To investigate the acetylation of Cdc25A.
- To identify the enzymes responsible for Cdc25A acetylation and deacetylation.
- To determine the functional consequences of Cdc25A acetylation in response to DNA damage.
Main Methods:
- Biochemical assays to demonstrate direct interaction and acetylation of Cdc25A by ARD1.
- Cell-based assays in cultured cells to confirm ARD1-mediated acetylation.
- Identification of HDAC11 as a Cdc25A deacetylase.
- Treatment with genotoxicants (MMS, etoposide, arsenic) to study acetylation changes.
Main Results:
- First evidence showing Cdc25A can be acetylated.
- ARD1 directly interacts with and acetylates Cdc25A.
- Acetylation extends Cdc25A half-life.
- HDAC11 identified as a Cdc25A deacetylase.
- DNA damage significantly increases Cdc25A acetylation.
- Acetylation modulates Cdc25A phosphatase activity and cell cycle regulation.
Conclusions:
- Cdc25A acetylation is a novel posttranslational modification regulated by ARD1 and HDAC11.
- This acetylation influences Cdc25A stability, activity, and cell cycle function, particularly under DNA damage conditions.
- Dysregulation of Cdc25A, ARD1, and HDAC11 in cancer suggests a potential role for acetylation in carcinogenesis.
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