The Molecular Basis of Cell Cycle Regulation

  Working with Saccharomyces cerevisiae, geneticist Leland Hartwell undertook a search for mutants that were ¡°stuck¡± at some point in the cell cycle. They were conditional mutants, mutants whose defect is apparent only under certain conditions - in Hartwell¡¯s case, at temperatures above the normal range for the organism. A yeast cell with such a temperature-sensitive mutation in a gene required for cell cycle operation reproduces normally at 20-23¡É but poorly or not at all at 35-37¡É. How can the mutant behave normally under permissive conditions? Presumably the protein encoded by the mutated gene is close enough to the normal gene product to function at the lower temperature, while the increased thermal energy at higher temperatures disrupts its active conformation more readily than that of the normal protein.

  In this way, Hartwell and his colleagues identified many genes involved in the cell cycle of S. cerevisiae and established the points in the cell cycle at which their products functioned. Predictably, some of these genes turned out to encode DNA replication proteins, but others seemed to function in cell cycle regulation.

  A breakthrough discovery was made by Paul Nurse and his colleagues, who carried out similar research with the fission yeast Schizosaccharomyces pombe. They identified a gene called cdc2 whose activity was essential for the initiation of mitosis - that is, for passing the G2 checkpoint. The acronym cdc stands for cell division cycle. The cdc2 gene turned out to be essentially identical to a S. cerevisiae gene that Hartwell¡¯s group had called CDC28 and to have counterparts in all eukaryotic cells. It was Nurse who showed that the human version of the gene could ¡°rescue¡± mutant yeast cells. In tribute to the importance of Nurse¡¯s discovery, the protein encoded by such a gene is often called a Cdc2 protein, regardless of the organism where it is found. Now, the generic term for a member of the Cdc2 protein family is cyclin-dependent protein kinase (Cdk).

  The various types of Cdk and cyclins act in different combinations at different stages of the animal cell cycle. The details are still being determined, but current evidence supports the involvement of Cdk2-cyclin A at the S phase, Cdc2 along with cyclins B and A at the G2 checkpoint, and Cdk2, Cdk4, and Cdk5 along with cyclins E and D at the G1 checkpoint. The different cyclins are made during different phases of the cell cycle.

A Few Notes About Gene Names

  Somewhat confusingly, the systems of nomenclature and typhography used for genes are not entirely standardized, but differ with the organism. The names of genes are almost always italicized, but there is variation in the use of uppercase versus lowercase letters and the use of numbers versus letters.

  Yeast Genes. For fission yeasts, such as Schizosaccharomyces pombe, the gene name is written in lowercase, and numbers are used to distinguish between genes involved in the same area of cellular function. For example, cdc1 and cdc2 are two different genes involved in the cell division cycle. As illustrated by the ¡°cdc¡± in this example, acronyms or abbreviations of terms relating to the gene's function are usually the basis for the gene name. For budding yeasts, such as Saccharomyces cerevisiae, gene names are similar to those for fission yeasts, but they are written in uppercase letters. For example, CDC28 is the name of the S.cerevisiae gene that corresponds to S. pombe¡¯s cdc2. When referring to the protein product encoded by a yeast gene, the usual designation is the same as the gene name, but with only the first letter capitalized and without italics; thus the protein encoded by cdc2 is calld Cdc2.

  Bacterial Genes. For bacterial genes, lower case letters are used for the part of the gene name indicating the area of gene function and uppercase letters to identify the particular protein. For example, dnaA and dnaB are two genes involved in E. coli DNA replication. The protein encoded by the dnaA gene is referred to as the DnaA protein, as with yeast.

  Human Genes. For ¡°higher¡± organisms such as animals and plants, a variety of conventions are employed. Human genes generally follow the convention for budding yeasts, although the length of the gene name is more variable. For example, BRCA2 is one of two recently identified genes associated with susceptibility to breast cancer.