ORC and the intra-S-phase checkpoint: a threshold regulates Rad53p activation in S phase.

The intra-S-phase checkpoint in yeast responds to stalled replication forks by activating the ATM-like kinase Mec1 and the CHK2-related kinase Rad53, which in turn inhibit spindle elongation and late origin firing and lead to a stabilization of DNA polymerases at arrested forks. A mutation that destabilizes the second subunit of ...
the Origin Recognition Complex, orc2-1, reduces the number of functional replication forks by 30% and severely compromises the activation of Rad53 by replication stress or DNA damage in S phase. We show that the restoration of the checkpoint response correlates in a dose-dependent manner with the restoration of pre-replication complex formation in G1. Other forms of DNA damage can compensate for the reduced level of fork-dependent signal in the orc2-1 mutant, yet even in wild-type cells, the amount of damage required for Rad53 activation is higher in S phase than in G2. Our data suggest the existence of an S-phase-specific threshold that may be necessary to allow cells to tolerate damage-like DNA structures present at normal replication forks.
Mesh Terms:
Cell Cycle Proteins, Cell Survival, Chromosomes, Fungal, Cycloheximide, DNA Damage, DNA Replication, DNA, Fungal, DNA-Binding Proteins, Dose-Response Relationship, Drug, Fungal Proteins, Gene Expression Regulation, Fungal, Genes, cdc, Hydroxyurea, Methyl Methanesulfonate, Mutation, Nucleic Acid Conformation, Origin Recognition Complex, Phosphorylation, Protein Synthesis Inhibitors, Protein-Serine-Threonine Kinases, Replication Origin, S Phase, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Ubiquitin
Genes Dev.
Date: Dec. 15, 2002
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