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GENES & DEVELOPMENT 22:1906-1920, 2008
©2008 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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Rad53 regulates replication fork restart after DNA damage in Saccharomyces cerevisiae

Shawn J. Szyjka, Jennifer G. Aparicio, Christopher J. Viggiani, Simon Knott, Weihong Xu1, Simon Tavaré, and Oscar M. Aparicio2

Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089, USA

Replication fork stalling at a DNA lesion generates a damage signal that activates the Rad53 kinase, which plays a vital role in survival by stabilizing stalled replication forks. However, evidence that Rad53 directly modulates the activity of replication forks has been lacking, and the nature of fork stabilization has remained unclear. Recently, cells lacking the Psy2–Pph3 phosphatase were shown to be defective in dephosphorylation of Rad53 as well as replication fork restart after DNA damage, suggesting a mechanistic link between Rad53 deactivation and fork restart. To test this possibility we examined the progression of replication forks in methyl-methanesulfonate (MMS)-damaged cells, under different conditions of Rad53 activity. Hyperactivity of Rad53 in pph3{Delta} cells slows fork progression in MMS, whereas deactivation of Rad53, through expression of dominant-negative Rad53-KD, is sufficient to allow fork restart during recovery. Furthermore, combined deletion of PPH3 and PTC2, a second, unrelated Rad53 phosphatase, results in complete replication fork arrest and lethality in MMS, demonstrating that Rad53 deactivation is a key mechanism controlling fork restart. We propose a model for regulation of replication fork progression through damaged DNA involving a cycle of Rad53 activation and deactivation that coordinates replication restart with DNA repair.

[Keywords: DNA replication fork; DNA damage; DNA repair; cell cycle checkpoint; BrdU; phosphatase; microarray]

Received February 6, 2008; revised version accepted May 14, 2008.

1 Present address: Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA.

2 Corresponding author.

E-MAIL oaparici{at}usc.edu; FAX (213) 740-8631.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1660408.


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