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G1/S transcription and the DNA synthesis checkpoint: common regulatory mechanisms
Tsvetomira Ivanova1, Blanca Gómez-Escoda, Elena Hidalgo
1Oxidative Stress and Cell Cycle Group, Universitat Pompeu Fabra, Barcelona, Spain.
Abstract:
When DNA replication is challenged, cells activate a DNA-synthesis checkpoint blocking cell cycle progression until they are able to overcome the replication defects. In fission yeast, Cds1 is the effector kinase of this checkpoint, inhibiting M phase entry through inactivation of the phosphatase Cdc25, stabilizing stalled replication forks to prevent deleterious DNA structures and triggering transcriptional activation of S-phase genes. The MBF complex controls the transcription of genes required for the S phase and Yox1, a homeodomain-containing protein, binds and represses MBF-dependent transcription at the end of S phase in a cell cycle-regulated manner. Interestingly, when the DNA synthesis checkpoint is activated, Yox1 is phosphorylated by Cds1 resulting in the abrogation of its binding to MBF. As a consequence, MBF-dependent transcription is maintained active until cells are able to overcome the replication challenge. Thus, Yox1 couples normal cell cycle regulation and the DNA synthesis checkpoint in a single transcriptional complex.
Insights
The DNA synthesis checkpoint in fission yeast uses Cds1 kinase to phosphorylate Yox1, preventing it from repressing S-phase gene transcription. This ensures cell cycle progression continues until DNA replication errors are resolved.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Cells possess a DNA synthesis checkpoint to halt cell cycle progression during replication stress.
- In fission yeast, Cds1 kinase regulates this checkpoint by inhibiting Cdc25 phosphatase and stabilizing replication forks.
- The MBF complex controls S-phase gene transcription, and Yox1 protein represses MBF activity at the end of S phase.
Purpose of the Study:
- To investigate the role of Yox1 in the DNA synthesis checkpoint.
- To elucidate the mechanism by which Yox1 couples normal cell cycle regulation with checkpoint control.
Main Methods:
- Utilized fission yeast as a model organism.
- Investigated protein-protein interactions between Yox1 and MBF.
- Analyzed the effect of Cds1 phosphorylation on Yox1 binding to MBF.
- Examined the transcriptional regulation of S-phase genes under checkpoint activation.
Main Results:
- Cds1 phosphorylates Yox1 upon activation of the DNA synthesis checkpoint.
- Phosphorylation of Yox1 by Cds1 abrogates its binding to the MBF complex.
- This prevents the repression of MBF-dependent transcription, maintaining S-phase gene expression.
- Yox1 acts as a crucial link between cell cycle progression and the DNA synthesis checkpoint.
Conclusions:
- Yox1's interaction with MBF is regulated by the Cds1-mediated DNA synthesis checkpoint.
- This regulatory mechanism ensures the continued transcription of essential S-phase genes during replication stress.
- Yox1 integrates cell cycle control with checkpoint signaling through a transcriptional complex.
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