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RESEARCH PAPER
1 Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom; 2 Cancer Research Institute, University of Salamanca/CSIC, 37007 Salamanca, Spain
Eukaryotic cells regulate the progression and integrity of DNA replication forks to maintain genomic stability and couple DNA synthesis to other processes. The budding yeast proteins Mrc1 and Tof1 associate with the putative MCM–Cdc45 helicase and limit progression of the replisome when nucleotides are depleted, and the checkpoint kinases Mec1 and Rad53 stabilize such stalled forks and prevent disassembly of the replisome. Forks also pause transiently during unperturbed chromosome replication, at sites where nonnucleosomal proteins bind DNA tightly. We describe a method for inducing prolonged pausing of forks at protein barriers assembled at unique sites on a yeast chromosome, allowing us to examine for the first time the effects of pausing upon replisome integrity. We show that paused forks maintain an intact replisome that contains Mrc1, Tof1, MCM–Cdc45, GINS, and DNA polymerases 
and 
and that recruits the Rrm3 helicase. Surprisingly, pausing does not require Mrc1, although Tof1 and Csm3 are both important. In addition, the integrity of the paused forks does not require Mec1, Rad53, or recombination. We also show that paused forks at analogous barriers in the rDNA are regulated similarly. These data indicate that paused and stalled eukaryotic replisomes resemble each other but are regulated differently.
[Keywords: DNA replication forks; Mrc1; Tof1; Csm3; checkpoint; recombination]
Received January 17, 2005; revised version accepted June 17, 2005.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.337205.
3 These authors contributed equally to this work.
E-MAIL klabib{at}picr.man.ac.uk; FAX 44-161-446-3109.
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