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MBC in Press, published online ahead of print April 2, 2008
Mol. Biol. Cell 10.1091/mbc.E07-08-0737

A more recent version of this article appeared on June 1, 2008
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Submitted on August 2, 2007
Revised on March 19, 2008
Accepted on March 20, 2008

Cds1 Controls the Release of Cdc14-like Phosphatase Flp1 from the Nucleolus to Drive Full Activation of the Checkpoint Response to Replication Stress in Fission Yeast

Helena Díaz-Cuervo and Avelino Bueno

Instituto de Biología Molecular y Celular del Cáncer, Departamento de Microbiología y Genética, Campus "Miguel de Unamuno", Universidad de Salamanca/CSIC, 37007 Salamanca, Spain

Monitoring Editor: Fred Chang

The Cdc14p-like phosphatase Flp1p (also known as Clp1p) is regulated by cell cycle-dependent changes in its subcellular localization. Flp1p is restricted to the nucleolus and SPB until prophase, when it is dispersed throughout the nucleus, mitotic spindle and medial ring. Once released, Flp1p antagonizes Cdc2p/cyclin activity by reverting Cdc2p-phosphorylation sites on Cdc25p. On replication stress, ATM/ATR-related kinase Rad3p activates Cds1p which phosphorylates key proteins ensuring the stability of stalled DNA replication forks. Here we show that replication stress induces changes in the subcellular localization of Flp1p in a checkpoint dependent manner. Active Cds1p checkpoint kinase is required to release Flp1p into the nucleus. Consistently, a Flp1p mutant (flp1–9A) lacking all potential Cds1p phosphorylation sites fails to relocate in response to replication blocks and, similarly to cells lacking flp1 ({Delta}flp1), presents defects in checkpoint response to replication stress. {Delta}flp1 cells accumulate reduced levels of a less active Cds1p kinase in hydroxyurea (HU), indicating that nuclear Flp1p regulates Cds1p full activation. Consistently, {Delta}flp1 and flp1–9A have an increased percentage of Rad22p-recombination foci during HU treatment. Taken together, our data show that by releasing Flp1p into the nucleus Cds1p checkpoint kinase modulates its own full activation during replication stress.

Address correspondence to: Avelino Bueno (abn{at}usal.es)






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