Cell cycle

The cell cycle, or cell-division cycle (CDC), is the series of events in a eukaryotic cell between one cell division and the next. It consists of four phases: G₁ phase, S phase, G₂ phase (collectively known as interphase) and M phase. M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm physically divides. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G₀ phase, while cells that have permanently stopped dividing due to age or accumulated DNA damage are said to be senescent.

The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle. There are two key classes of regulatory molecules that determine a cell's progress through the cell cycle: cyclins and cyclin-dependent kinases. Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules in the regulation of the cell cycle.

Phases of the cell cycle

Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for entry into the next stage. It should be remembered that, throughout interphase, the cell carries out its normal metabolic activities and is actively engaging in transcription and translation of its genome.

In G₁ phase, the cell carries on its usual metabolic activities while preparing to duplicate its DNA. These preparations often include growing by increasing the amount of cytoplasm and the number of important organelles such as mitochondria. (This is particularly important in organisms and cell types that divide their cytoplasm unevenly, as in budding yeast.) In G₁ a diploid cell (such as a human cell) has a complement of 2N chromosomes, where N is the gene copy number; in sexually reproducing organisms this amounts to one chromosome inherited from each parent. The actual quantity of DNA is described as 2c, where the "c" value is measured in picograms and 1c is equal to the quantity of DNA in a single haploid genome. The end of G₁ is demarcated by a "point of no return" beyond which the cell is committed to dividing; in yeast this is called START and in multicellular eukaryotes it is termed the restriction point.
In S phase, the cell duplicates its DNA.
In G₂ phase, the cell continues with growth and metabolism in preparation for undergoing mitosis. In this quantity of DNA within the cell has increased to 4c, but the cell is still considered diploid.
In M phase the cell segregates its chromosomes so that both daughter cells receive a total complement of 2N. The four stages of mitosis - prophase, metaphase, anaphase, and telophase - also progress in a sequential and directional fashion, like the cell cycle as a whole. Telophase, the final stage of mitosis, is accompanied by cytokinesis; when the cytoplasm is completely divided, the cycle is complete and the new daughter cells are said to be in G₁ again. The exact mechanism of cytokinesis is highly organism- and cell type-dependent; for example, in plant cells surrounded by a rigid cell wall, cytokinesis occurs via the formation of a cell plate, while animal cells are "pinched" in two by a ring formed from a structural protein called actin.

Although the illustration assigns the four stages of the cell cycle roughly equal durations, a cell actually spends a very small amount of its time in M phase. The overall duration of the cell cycle depends on the organism and type of cell.

The term "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G₀ state from G₁ and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis.

Cyclins and cyclin-dependent kinases

Cyclins and cyclin-dependent kinases (CDKs) are the two critical classes of molecules in regulation of cell cycle progression. Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted.

Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified studying yeast, especially Saccharomyces cerevisiae; genetic nomenclature in yeast dubs many of these genes cdc (for "cell division cycle") followed by an identifying number, e.g., cdc28. In the following discussion generic names such as "S cyclin" will be used to maintain generality, with the understanding that this may refer to one or to several homologous molecules in any given organism, and that some organisms may combine multiple functions in one molecule.

Upon receiving a pro-mitotic extracellular signal, G₁ cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G₁ cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome.

Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G₁ phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes would also prove deleterious to the daughter cells.

Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G₂ phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.

Checkpoints

A molecular surveillance system monitors the cell's progress through the cell cycle and halts progression if extensive DNA damage has occurred or if a key event, such as the attachment of a chromosome to the mitotic spindle, has not occurred properly. These checkpoints help to ensure that a cell divides only when it has completed all of the molecular prerequisites for producing healthy daughter cells.

Three key stages of progression through the cell cycle involve the degradation of signaling molecules and are therefore irreversible; passage through these checkpoints not only "certifies" that the cell is capable of proceeding to the next step, but also commits the cell to that process. The restriction point that marks the transition from G₁ to S phase is the first such transition; the others occur between metaphase and anaphase (the spindle checkpoint) and between anaphase and telophase when mitotic cyclins are degraded.

The full system of checkpoints also includes monitoring of the cell's DNA for unrepaired damage and for successful completion of replication.

There are four DNA-damage checkpoints regulated primarily by the protein p53: one during G₁, one at the entry into S phase, one near the end of S phase, and one at the entry into M phase.
The unreplicated DNA checkpoint that occurs at the entry into M phase ensures that the cell has successfully and completely replicated its genome.
The spindle-assembly checkpoint occurs during anaphase and checks that all chromosomes have successfully attached to the mitotic spindle.
The chromosome-segregation checkpoint in telophase ensures that the chromosomes have properly migrated to the cell poles and that the cell is ready for cytokinesis and exit from mitosis.

The DNA-damage checkpoint protein p53 has been implicated in a large number of human cancers because its absence allows the cell to proceed into S phase with unrepaired DNA damage that leads to mutations when the DNA replication machinery misinterprets the damaged region or uses a lossy DNA repair mechanism to avoid the more serious consequence of proceeding through the cell cycle with a partially unreplicated genome. Very few of these mutations would by themselves be troublesome, but their continued accumulation in p53-deficient cell lineages produces a high likelihood of introducing mutations in oncogenes, many of which are associated with controlling cell division and preventing unconstrained growth. p53 also serves as a mechanism to induce apoptosis, or "cell suicide", in cases where the cell has sustained irreparably high amounts of DNA damage.

References

Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Biology of the Cell. WH Freeman: New York, NY. 5th ed.
Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R. (2004). Molecular Biology of the Gene, ch. 7. Peason Benjamin Cummings; CSHL Press. 5th ed.

External links

Cell biology | Cell cycle

Gourt Home::Gourt :: Cell cycle

Phases of the cell cycle

Cyclins and cyclin-dependent kinases

Checkpoints

References

See also

External links