Yeast protein phosphatase Ptc1 in the regulation of the cell cycle S-phase

Abstract

Phosphorylation state of any protein is the result of a balance between the activities of kinases and phosphatases (PPases), that can modify the protein functions. Recently due to a better understanding of the regulatory mechanisms of the cell cycle, there is a growing appreciation for the role of PPases in this process, since the coordination of cell growth with division is essential for genomic stability and proper cell function. Checkpoints are mechanisms designed to ensure correct transmission of genetic information during the cell cycle. The normal role of S-phase checkpoint is to suppress the genome rearrangements resulting from aberrant repair of DNA damage during replication or from the misfiring of origins of replication. The Ptc1 protein is the most relevant PPase of the PP2C family in Saccharomyces cerevisiae. Evidences demonstrated relationship between Ptc1 and the cell wall integrity signaling pathway (CWI) pathway, responsible for proper remodeling of the cell wall, due the phosphorylation of Slt2. Loss of Ptc1 results in cells with increased amounts of active Slt2 and higher expression of genes regulated by it. Stl2 has been involved in the regulation of genes during G1/S transition of the mitotic cell cycle and others. Ptc1 also directly dephosphorylates and inactive Mkk1 (main kinase "upstream" to Slt2). Deletion of Mkk1 or Slt2 overcome most of the defects observed in ptc1 cells (great sensitivity to stress conditions), indicating that these defects were caused by constitutive hyperactivation of the Slt2. In this way, the proposed project aims to evaluate the functional mechanisms of Ptc1 from S. cerevisiae in the regulation of S-phase cell cycle, due the influence of Ptc1 on the Slt2 deactivation. The identification of new players in the S-phase checkpoint of eukaryotic cells can contribute insights into the mechanisms leading to genomic rearrangements, providing initial key points for studies related not only to fungal virulence/antifungal resistance but, because of the conservation of the system in humans, also to development of cancer.