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Vol. 19, Issue 2, 595-607, February 2008

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RFC^Ctf18 and the Swi1-Swi3 Complex Function in Separate and Redundant Pathways Required for the Stabilization of Replication Forks to Facilitate Sister Chromatid Cohesion in Schizosaccharomyces pombe

Alison B. Ansbach^*, Chiaki Noguchi^*, Ian W. Klansek^*, Mike Heidlebaugh^*, Toru M. Nakamura, and Eishi Noguchi^*

*Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102; and Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607

Submitted June 28, 2007; Revised November 9, 2007; Accepted November 19, 2007
Monitoring Editor: Mark Solomon

Sister chromatid cohesion is established during S phase near the replication fork. However, how DNA replication is coordinated with chromosomal cohesion pathway is largely unknown. Here, we report studies of fission yeast Ctf18, a subunit of the RFC^Ctf18 replication factor C complex, and Chl1, a putative DNA helicase. We show that RFC^Ctf18 is essential in the absence of the Swi1–Swi3 replication fork protection complex required for the S phase stress response. Loss of Ctf18 leads to an increased sensitivity to S phase stressing agents, a decreased level of Cds1 kinase activity, and accumulation of DNA damage during S phase. Ctf18 associates with chromatin during S phase, and it is required for the proper resumption of replication after fork arrest. We also show that chl1 is synthetically lethal with ctf18 and that a dosage increase of chl1⁺ rescues sensitivities of swi1 to S phase stressing agents, indicating that Chl1 is involved in the S phase stress response. Finally, we demonstrate that inactivation of Ctf18, Chl1, or Swi1-Swi3 leads to defective centromere cohesion, suggesting the role of these proteins in chromosome segregation. We propose that RFC^Ctf18 and the Swi1–Swi3 complex function in separate and redundant pathways essential for replication fork stabilization to facilitate sister chromatid cohesion in fission yeast.

Address correspondence to: Eishi Noguchi (enoguchi{at}drexelmed.edu)

Abbreviations used: CPT, camptothecin; FPC, fork protection complex; HU, hydroxyurea; MMS, methylmethane sulfonate; PCNA, proliferating cell nuclear antigen; PFGE, Pulsed field gel electrophoresis; RFC, replication factor C; TBZ, thiabendazole.