The study of the cell cycle focuses on mechanisms that regulate the timing and frequency of DNA duplication and cell division. As a biological concept, the cell cycle is defined as the period between successive divisions of a cell. During this period, the contents of the cell must be accurately replicated. Microscopists had known about cell division for more than one hundred years, but not until the 1950s, through the pioneering work of Alma Howard and Stephen Pelc, did they become aware that DNA replication took place only at a specific phase of the cell cycle and that this phase was clearly separated from mitosis. Howard and Pelc's work in the broad bean, Vicia faba, revealed that the cell goes through many discrete phases before and after cell division. From this understanding, scientists then identified the four characteristic phases of the cell cycle: mitosis (M), gap 1 (G1), DNA synthesis (S), and gap 2 (G2). The study of these phases, the proteins that regulate them, and the complex biochemical interactions that stop or start DNA replication and cell division (cytokinesis) are the primary concerns of cell cycle biologists. The most significant progress in this research field came with the demonstration that specific protein complexes involving cyclins were critical for regulating the passage of cells through the cell cycle. These early observations came from biological studies of the cells of rapidly dividing fertilized frog eggs as well as mutant yeast cells that could not divide. The observations suggested that regulation of the cell cycle is conserved throughout eukaryotes, which has since proved to be the case. The mechanism of division in bacteria differs from that of eukaryotes, and the control of their cell cycle is also somewhat different, although again it is linked with DNA replication. Although the cell cycle is a highly integrated process, distinct areas of interest within this field of study have emerged. For instance, many genes and proteins that influence the passage from one phase of the cell cycle to another have been identified. When their expression is altered by mutation or aberrant regulation, they are usually classed as oncogenes. Other proteins act to hold the cell at distinct points in the cycle (checkpoints) and are known as tumor suppressor genes. Apart from those with a clearly regulatory role, many proteins have important functions in other aspects of the cell cycle; one is replication of DNA and organelles, which is a fascinating process that includes its own repair mechanisms and self-editing. Other fields focus primarily on themechanical processes of cell cleavage into two daughter cells at the end of mitosis and on the condensation and decondensation of chromatin. How does the cell cycle affect our daily lives? Indeed, most cancers are the result of inappropriate cell division, often stemming from aberrations in normal cell cycle regulation. Considerable research is directed to identifying alterations in cell cycle regulatory proteins, both as targets for therapeutic intervention and as biomarkers that may indicate prognoses for tumors. In addition, the field of stem cell biology is closely linked to cell cycle regulation because these pluripotent cells can divide slowly over long periods and yet initiate growth and differentiation when required. Other areas of current research include investigating cell cycle regulation in the growth of organs and in regeneration, where dormant cells can be switched back into a replicative state. How have scientists studied the cell cycle? Originally, cell cycle studies were the preserve of microscopy, but today many specific techniques in addition to those widely employed in cell and molecular biology are applied. Fluorescence-activated cell sorting has allowed biologists to both identify cells at particular points of the cell cycle and isolate them. It is possible to monitor how cells that have been exposed to different agents can progress through the cycle. Central to the identification and isolation of key genes has been the ability to isolate temperature-sensitive mutant yeast cells that can be blocked at certain stages of the cycle for closer study. The ability to synchronize cultures so that all cells are at the same point in the cell cycle has also been a boon to capturing a glimpse of common mechanisms and isolating key proteins. Although we now know much about the regulation of the cell cycle, it is clear that we have a long way to go, particularly in understanding the complexity of the interactions between the vast multitude of proteins already identified. Current research has identified a large number of signaling pathways, many comprising several genes, involved in regulating progression through the cycle. Several of these pathways can interact, and knowledge of these interactions will be vital to developing effective strategies for intervention in cancer and other growth abnormalities, such as developmental deformities. In addition, how the cell cycle responds to DNA damage is an area of active research because random aberrations in replication and even environmental toxins can affect vulnerable DNA strands. Ultimately, the success of stem cell-based therapies will depend on a detailed knowledge of how cells can be maintained through many divisions without losing their potential to differentiate or transform into tumor precursors. The study of the cell cycle has vast relevance to the health, well-being, and biology of all organisms, from the growth and development of these organisms, to cancer and aging humans, to the potential for disease and injury repair via stem cell therapies.
Via Dr. Stefan Gruenwald
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