Related Experiment Video

Updated: Feb 14, 2026

Recombinant α- β- and γ-Synucleins Stimulate Protein Phosphatase 2A Catalytic Subunit Activity in Cell Free Assays
09:36

Recombinant α- β- and γ-Synucleins Stimulate Protein Phosphatase 2A Catalytic Subunit Activity in Cell Free Assays

Published on: August 13, 2017

7.1K

HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130

Anja Göder1, Claudia Emmerich2, Teodora Nikolova1

  • 1Institute of Toxicology, University Medical Center Mainz, Obere Zahlbacher Strasse 67, 55131, Mainz, Germany.

Nature Communications
|February 24, 2018
PubMed

Insights

Histone deacetylases HDAC1/HDAC2 maintain DNA replication checkpoints. Inhibiting HDACs during replication stress causes cell death, revealing HDACs

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Checkpoint kinases are crucial for sensing DNA replication stress and preventing genomic instability.
  • Histone deacetylases (HDACs) play roles in gene regulation and cellular processes, but their specific involvement in DNA replication stress response is not fully elucidated.
  • Understanding the molecular mechanisms governing DNA replication checkpoints is vital for cancer therapy development.

Purpose of the Study:

  • To investigate the role of histone deacetylases HDAC1 and HDAC2 in maintaining DNA replication checkpoints.
  • To elucidate the molecular mechanisms by which HDAC1/HDAC2 regulate checkpoint kinases and cell fate decisions under replicative stress.
  • To determine the impact of HDAC inhibition on cellular responses to DNA replication stress.

Main Methods:

  • Western blotting to assess protein phosphorylation and levels.
  • Genetic manipulation (e.g., gene ablation) to study the function of PR130.
  • Cell cycle analysis and DNA damage assays.
  • Analysis of apoptosis and homologous recombination.
  • HDAC inhibition treatments.

Main Results:

  • HDAC1/HDAC2 sustain phosphorylation of ATM, CHK1, CHK2, WEE1, CDK1, and p53 during stalled DNA replication.
  • HDAC1/HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of protein phosphatase 2A (PP2A).
  • PR130 promotes ATM dephosphorylation by PP2A; its ablation leads to increased DNA damage and sensitivity to HDAC inhibition.

Conclusions:

  • HDAC1/HDAC2 are essential for sustaining DNA replication checkpoints by regulating key signaling proteins and suppressing PR130.
  • HDAC inhibition during replicative stress abrogates the S phase checkpoint, leading to mitotic catastrophe and apoptosis.
  • PR130 acts as a critical regulator of cell fate decisions in response to replicative stress, influencing susceptibility to HDAC inhibition.

More Related Videos

Monitoring Kinase and Phosphatase Activities Through the Cell Cycle by Ratiometric FRET13:38

Monitoring Kinase and Phosphatase Activities Through the Cell Cycle by Ratiometric FRET

Published on: January 27, 2012

14.7K
Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay12:26

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

19.4K

Related Concept Videos

Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
15.2K
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

4.5K
Phosphorylation01:02

Phosphorylation

The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
54.4K
The Spindle Assembly Checkpoint02:19

The Spindle Assembly Checkpoint

The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
3.9K
Fates of Pyruvate01:20

Fates of Pyruvate

Pyruvate is the end product of glycolysis, where glucose is oxidized to pyruvate, simultaneously reducing NAD+ to NADH. Two molecules of ATP are also produced by substrate-level phosphorylation.
In aerobic organisms, pyruvate is metabolized via the citric acid cycle to produce reduced coenzymes NADH and FADH2. These coenzymes are then oxidized in the electron transport chain to produce ATP and, in the process, regenerate the NAD+ and FAD. As seen in some cell types and organisms, fermentation...
11.2K
Intracellular Signaling Cascades01:24

Intracellular Signaling Cascades

Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. The continuation of a signal in this manner is called signal transduction. Signal transduction only occurs with cell-surface receptors, which cannot interact with most components of the cell, such as DNA. Only internal receptors can interact directly with DNA in the nucleus to initiate protein synthesis. When a ligand binds to its receptor, conformational changes occur that affect the...
53.7K