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Molecular and Cellular Biology, January 2009, p. 602-611, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01319-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Checkpoint-Dependent Regulation of Origin Firing and Replication Fork Movement in Response to DNA Damage in Fission Yeast {triangledown}

Sanjay Kumar{dagger} and Joel A. Huberman*

Department of Cancer Biology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263-0001

Received 19 August 2008/ Returned for modification 16 September 2008/ Accepted 30 October 2008

To elucidate the checkpoint mechanism responsible for slowing passage through S phase when fission yeast cells are treated with the DNA-damaging agent methyl methanesulfonate (MMS), we carried out two-dimensional gel analyses of replication intermediates in cells synchronized by cdc10 block (in G1) followed by release into synchronous S phase. The results indicated that under these conditions early-firing centromeric origins were partially delayed but late-firing telomeric origins were not delayed. Replication intermediates persisted in MMS-treated cells, suggesting that replication fork movement was inhibited. These effects were dependent on the Cds1 checkpoint kinase and were abolished in cells overexpressing the Cdc25 phosphatase, suggesting a role for the Cdc2 cyclin-dependent kinase. We conclude that both partial inhibition of the firing of a subset of origins and inhibition of replication fork movement contribute to the slowing of S phase in MMS-treated fission yeast cells.

* Corresponding author. Mailing address: Department of Cancer Biology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263-0001. Phone: (716) 845-3047. Fax: (716) 845-8126. E-mail: huberman{at}buffalo.edu

{triangledown} Published ahead of print on 10 November 2008.

{dagger} Present address: Division of Biology, MC 147-75, California Institute of Technology, 1200 E. California Blvd., Pasadena, CA 91125.

Molecular and Cellular Biology, January 2009, p. 602-611, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01319-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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