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Viral cyclin-cyclin-dependent kinase 6 complexes initiate nuclear DNA replication
1Gene Regulation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.
Molecular and Cellular Biology
|January 3, 2001
Summary
Viral cyclins complexed with cdk6 exhibit unique properties, driving DNA synthesis initiation. These viral cyclin-cdk6 complexes function as both G1-phase and S-phase regulators, distinct from human D-type cyclins.
Area of Science:
- Virology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Kaposi sarcoma-associated herpesvirus and herpesvirus saimiri encode viral cyclins that are homologs of human D-type cyclins.
- Viral cyclin-cdk6 complexes display distinct activities compared to human cyclin D-cdk6 complexes, including inhibitor resistance and broader substrate specificity.
Purpose of the Study:
- To investigate the functional activities of viral cyclin-cdk6 complexes in DNA replication.
- To determine if viral cyclin-cdk6 complexes can directly initiate DNA synthesis.
- To compare the functions of viral cyclin-cdk6 complexes with known cell cycle regulators.
Main Methods:
- Complex formation and in vitro kinase assays.
- Phosphorylation analysis of replication initiation proteins.
- Mammalian in vitro replication systems using isolated late-G1-phase nuclei.
Main Results:
- Viral cyclin-cdk6 complexes phosphorylate proteins crucial for replication initiation.
- These viral complexes directly trigger DNA synthesis initiation in late-G1-phase nuclei.
- Viral cyclin-cdk6 complexes demonstrated S-phase activity, similar to cyclin A-cdk2.
Conclusions:
- Viral cyclin-cdk6 complexes possess unique biochemical properties and functional capabilities.
- Viral cyclins can drive DNA replication initiation, acting as both G1 and S phase regulators.
- These findings reveal novel mechanisms of viral manipulation of host cell cycle machinery for replication.
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