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Vol. 20, Issue 15, 3572-3582, August 1, 2009

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The Stress-activated Protein Kinase Hog1 Mediates S Phase Delay in Response to Osmostress

Gilad Yaakov^*, Alba Duch^*,, María García-Rubio^,, Josep Clotet^*,, Javier Jimenez^*, Andrés Aguilera, and Francesc Posas^*

*Cell Signaling Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain; Centro Andaluz de Biología Molecular and Medicina Regenativa, Universidad de Sevilla-Consejo Superior de Investigaciones Cientificas, 41092 Sevilla, Spain; and Department of Molecular and Cellular Biology, Universitat Internacional de Catalunya, 08190 Sant Cugat del Vallès, Spain

Submitted February 12, 2009; Revised May 14, 2009; Accepted May 20, 2009
Monitoring Editor: Charles Boone

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. Exposure of yeast to osmostress activates the Hog1 SAPK, which modulates cell cycle progression at G1 and G2 by the phosphorylation of elements of the cell cycle machinery, such as Sic1 and Hsl1, and by down-regulation of G1 and G2 cyclins. Here, we show that upon stress, Hog1 also modulates S phase progression. The control of S phase is independent of the S phase DNA damage checkpoint and of the previously characterized Hog1 cell cycle targets Sic1 and Hsl1. Hog1 uses at least two distinct mechanisms in its control over S phase progression. At early S phase, the SAPK prevents firing of replication origins by delaying the accumulation of the S phase cyclins Clb5 and Clb6. In addition, Hog1 prevents S phase progression when activated later in S phase or cells containing a genetic bypass for cyclin-dependent kinase activity. Hog1 interacts with components of the replication complex and delays phosphorylation of the Dpb2 subunit of the DNA polymerase. The two mechanisms of Hog1 action lead to delayed firing of origins and prolonged replication, respectively. The Hog1-dependent delay of replication could be important to allow Hog1 to induce gene expression before replication.

These authors contributed equally to this work.

Address correspondence to: Francesc Posas (francesc.posas{at}upf.edu)