A central role for DNA replication forks in checkpoint activation and response

Mol Cell. 2003 May;11(5):1323-36. doi: 10.1016/s1097-2765(03)00169-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • CDC45 protein, S cerevisiae
  • CDC6 protein, S cerevisiae
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Saccharomyces cerevisiae Proteins
  • metronidazole monosuccinate
  • Metronidazole
  • CDC7 protein, S cerevisiae
  • Checkpoint Kinase 2
  • MEC1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases
  • RAD53 protein, S cerevisiae