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Vol. 16, No. 24, pp. 3236-3252, December 15, 2002
University of Geneva, Department of Molecular Biology CH-1211
Geneva 4, Switzerland
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.
[Key Words: Replication checkpoint; Rad53; ORC; yeast, DNA damage; S phase; Supplemental material is available at http://www.genesdev.org.]
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