title: A central role for DNA replication forks in checkpoint activation and response.
abstract: 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.
authors.affiliation: Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, United Kingdom.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Tercero
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Longhese
authors.forename: John F X
authors.initials: JF
authors.lastname: Diffley
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D018816:Genes, cdc / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008795:Metronidazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D008938:Mitosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016196:S Phase / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C102209:CDC45 protein, S cerevisiae; C066503:CDC6 protein, S cerevisiae; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C051964:metronidazole monosuccinate; D008795:Metronidazole; C489404:CDC7 protein, S cerevisiae; D064447:Checkpoint Kinase 2; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae