Russell Lab Research Publications Members Alumni

Russell Lab Research Summary TSRI Scientific Reports [ 1997 | 1998 | 1999 | 2000 | 2001 | 2002 | 2003 | 2004 | 2005| 2006 | 2007] Regulation of the Cell Cycle     Our laboratory studies cell division; in particular, how the onset of mitosis is regulated. We use the fission yeast Schizosaccharomyces pombe as a model system. Mitosis is catalyzed by Cdc2, a cyclin-dependent kinase (CDK). Cdc2 is inhibited by phosphorylation carried out by the tyrosine kinases Wee1 and Mik1. Cdc2 is activated by Cdc25, and to a small degree by Pyp3, two tyrosine phosphatases. Activation of Cdc2 at the G2-M transition is thought to be accelerated by feedback loops that enhance activity of Cdc25 and inhibit Wee1. The mitotic control program determined by Wee1, Mik1, Cdc25 and Pyp3 is responsive to many different signals, including cell mass, ploidy, nutrient availability and stress.     Mitotic control also responds to checkpoint signals that restrain mitosis when DNA is unreplicated or damaged. These checkpoint mechanisms help to maintain genome integrity. The G2-M DNA damage checkpoint is enforced by the protein kinase Chk1, whereas the S-M replication checkpoint, which couples the onset of mitosis to the completion of DNA replication, is enforced by the protein kinase Cds1. Chk1 and Cds1 inhibit mitosis by phosphorylating Cdc25 and by regulating Mik1 abundance. Cds1 is also important for survival in circumstances that stall replication forks, such as when the replication apparatus encounters DNA damage or it is starved of deoxyribonucleotides.     Chk1 and Cds1 are regulated by proteins that act as checkpoint sensors or transducers. These proteins include the so called Checkpoint Rad proteins: Rad1, Rad3, Rad9, Rad17, Rad26, and Hus1. Cut5/Rad4 and Crb2/Rhp9 are also important for checkpoints. The functions of these proteins are poorly understood, but it is worth noting that Rad3 is a protein kinase and many of the checkpoint proteins undergo Rad3-dependent phosphorylation.     The goal of our research is to understand how the mitotic control responds to the diverse array of signals described above. We want to understand how cells respond to genotoxic stress caused by agents that damage DNA or inhibit DNA replication, as well as cytotoxic stress (e.g. oxidative or osmotic stress). We take advantage of the powerful range of genetic and biochemical methods that are used to investigate fission yeast. Bear in mind that most of the discoveries made with Schizosaccharomyces pombe are applicable to understanding similar processes in humans. Indeed, many of the proteins now known to regulate the cell cycle in humans, such as Cdc25, Wee1 and Chk1, were first uncovered in fission yeast. We anticipate that fission yeast studies will continue providing a valuable framework for understanding biological processes that are conserved amongst most eukaryotic organisms.      Fig. 1: Phenotypes of fission yeast cell-cycle mutants. Cells are stained with Calcafluor, which predominantly binds to the septum. Upper panel: A wild-type cell dividing at a cell length of about 14 mm. Middle panel: cdc25-22 mutant cells undergoing cell-cycle arrest. Lower panel: wee1-50 mutant cells dividing at approximately half the size of wild-type cells.

This site is maintained by Sophie Rozenzhak
E-mail: sophie@scripps.edu
Last modified April 2008

Site created by: Toru Nakamura