A Central Role for DNA Replication Forks in Checkpoint Activation and Response

The checkpoint proteins Rad53 and Mec1-Ddc2 regulate many aspects of cell metabolism in response to DNA damage. We have examined the relative importance of downstream checkpoint effectors on cell viability. Checkpoint regulation of mitosis, gene expression, and late origin firing make only modest co...

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Bibliographic Details
Published in:Molecular cell 2003-05, Vol.11 (5), p.1323-1336
Main Authors: Tercero, José Antonio, Longhese, Maria Pia, Diffley, John F.X
Format: Article
Language:English
Subjects:
Carrier Proteins - genetics
Cell Cycle Proteins - genetics
Cell Survival - genetics
Cells, Cultured
Checkpoint Kinase 2
DNA Replication - genetics
DNA-Binding Proteins
Gene Expression Regulation, Fungal - genetics
Genes, cdc - physiology
Intracellular Signaling Peptides and Proteins
Metronidazole - analogs & derivatives
Metronidazole - pharmacology
Mitosis - genetics
Nuclear Proteins - genetics
Protein Serine-Threonine Kinases - genetics
S Phase - genetics
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae Proteins - biosynthesis
Saccharomyces cerevisiae Proteins - genetics
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Summary:The checkpoint proteins Rad53 and Mec1-Ddc2 regulate many aspects of cell metabolism in response to DNA damage. We have examined the relative importance of downstream checkpoint effectors on cell viability. Checkpoint regulation of mitosis, gene expression, and late origin firing make only modest contributions to viability. By contrast, the checkpoint is essential for preventing irreversible breakdown of stalled replication forks. Moreover, recruitment of Ddc2 to nuclear foci and subsequent activation of the Rad53 kinase only occur during S phase and require the assembly of replication forks. Thus, DNA replication forks are both activators and primary effectors of the checkpoint pathway in S phase.
ISSN:1097-2765
1097-4164
DOI:10.1016/S1097-2765(03)00169-2