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Published on: October 27, 2011
Cdt1 and Cdc6 are destabilized by rereplication-induced DNA damage
Jonathan R Hall1, Hyun O Lee2, Brandon D Bunker1
1Department of Biochemistry and Biophysics, Chapel Hill, North Carolina 27599-7260.
The Journal of Biological Chemistry
|July 12, 2008
Summary
Cell cycle control factors Cdt1 and Cdc6 are degraded when DNA replication occurs abnormally. This degradation prevents extensive rereplication, acting as a conserved damage control mechanism.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Replication factors Cdt1 and Cdc6 are crucial for DNA replication initiation.
- Metazoan cells employ mechanisms like Cdt1 degradation and geminin inhibition to ensure single DNA replication per cell cycle.
- Disrupting these controls, such as through geminin depletion, leads to rereplication and DNA damage.
Purpose of the Study:
- To investigate the mechanisms that restrain rereplication once it begins.
- To understand the degradation pathways of Cdt1 and Cdc6 in response to rereplication-induced DNA damage.
Main Methods:
- Geminin depletion in human cells to induce rereplication.
- Analysis of Cdt1 and Cdc6 degradation pathways.
- Utilizing ubiquitin ligases Cul4(DDB1) and Huwe1.
- Investigating the role of the PCNA binding site of Cdt1.
- Experiments in human and Drosophila melanogaster cells.
Main Results:
- Both Cdt1 and Cdc6 are degraded in geminin-depleted cells.
- Cdt1 degradation requires its PCNA binding site and the Cul4(DDB1) ubiquitin ligase.
- Cdc6 degradation is mediated by the Huwe1 ubiquitin ligase.
- Disrupting Cdt1 and Cdc6 degradation exacerbates rereplication.
Conclusions:
- Rereplication-associated DNA damage triggers Cdt1 and Cdc6 ubiquitination and degradation.
- This pathway is an evolutionarily conserved mechanism to limit the extent of rereplication.
- Cellular safeguards involving Cdt1 and Cdc6 destruction protect against excessive DNA replication.
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