Related Experiment Video

Updated: Jun 30, 2026

Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
10:59

Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage

Published on: August 21, 2021

Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability

Laura L Pontano1, Priya Aggarwal, Olena Barbash

  • 1Department of Cancer Biology, The Abramson Family Cancer Research Institute, 454 BRB II/III, Philadelphia, PA 19104-6140, USA.

Molecular and Cellular Biology
|September 24, 2008
PubMed

Insights

Failure to degrade cyclin D1 (cell cycle regulator) after DNA damage can lead to genomic instability. This study reveals key pathways for cyclin D1 degradation, crucial for preventing errors during DNA repair.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin D1 accumulation promotes cell cycle progression.
  • Ubiquitin-mediated proteolysis normally limits cyclin D1 levels, preventing uncontrolled cell proliferation.
  • Failure to degrade cyclin D1 during S-phase can result in DNA rereplication.

Purpose of the Study:

  • To investigate the cellular regulation of cyclin D1 following genotoxic stress.
  • To understand the mechanisms underlying cyclin D1 degradation in response to DNA damage.
  • To determine the consequences of impaired cyclin D1 degradation on genomic stability.

Main Methods:

  • Analysis of cyclin D1 alleles resistant to degradation.
  • Investigating the role of ATM and GSK3beta in DNA double-strand break-dependent degradation.
  • Utilizing ubiquitylation assays with SCF(Fbx4-alphaBcrystallin) complex.
  • Assessing radio-resistant DNA synthesis and chromatid breaks.

Main Results:

  • Expression of degradation-resistant cyclin D1 alleles increased chromatid breaks post-DNA damage.
  • ATM and GSK3beta are required for double-strand break-induced cyclin D1 degradation via phosphorylation.
  • Phosphorylated cyclin D1 is ubiquitylated by SCF(Fbx4-alphaBcrystallin) and degraded by the proteasome.
  • Loss of Fbx4-dependent degradation led to radio-resistant DNA synthesis.

Conclusions:

  • Cyclin D1 degradation is essential for maintaining genomic stability after genotoxic insult.
  • Impaired cyclin D1 degradation compromises the intra-S-phase checkpoint.
  • Targeting Fbx4-dependent degradation sensitizes cells to S-phase-specific chemotherapy, suggesting therapeutic potential.

More Related Videos

Cell Cycle-specific Measurement of γH2AX and Apoptosis After Genotoxic Stress by Flow Cytometry08:21

Cell Cycle-specific Measurement of γH2AX and Apoptosis After Genotoxic Stress by Flow Cytometry

Published on: September 1, 2019

Studying Proteolysis of Cyclin B at the Single Cell Level in Whole Cell Populations10:54

Studying Proteolysis of Cyclin B at the Single Cell Level in Whole Cell Populations

Published on: September 17, 2012

Related Concept Videos

DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Positive Regulator Molecules02:39

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
Positive Regulator Molecules01:45

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.