The Cell Cycle
A eukaryotic cell cannot divide into two, the two into four, etc. unless two processes alternate: doubling of its genome (DNA) in S phase (synthesis phase) of the cell cycle; halving of that genome during mitosis (M phase).
The period between M and S is called G1; that between S and M is G2.
So, the cell cycle consists of:
G1 = growth and preparation of the chromosomes for replication; S = synthesis of DNA [see DNA Replication] and duplication of the centrosome; G2 = preparation for
M = mitosis.
When a cell is in any phase of the cell cycle other than mitosis, it is often said to be in interphase. Control of the Cell Cycle
The passage of a cell through the cell cycle is controlled by proteins in the cytoplasm. Among the main players in animal cells are: Cyclins
G1 cyclins (D cyclins)
S-phase cyclins (cyclins E and A)
mitotic cyclins (B cyclins)
Their levels in the cell rise and fall with the stages of the cell cycle. Cyclin-dependent kinases (Cdks)
a G1 Cdk (Cdk4)
an S-phase Cdk (Cdk2)
an M-phase Cdk (Cdk1)
Their levels in the cell remain fairly stable, but each must bind the appropriate cyclin (whose levels fluctuate) in order to be activated. They add phosphate groups to a variety of protein substrates that control processes in the cell cycle. The anaphase-promoting complex (APC). (The APC is also called the cyclosome, and the complex is often designated as the APC/C.) The APC/C triggers the events leading to destruction of cohesin (as described below) thus allowing the sister chromatids to separate; degrades the mitotic (B) cyclins.
Steps in the cycle
A rising level of G1-cyclins bind to their Cdks and signal the cell to prepare the chromosomes for replication. A rising level of S-phase promoting factor (SPF) — which includes A cyclins bound to Cdk2 — enters the nucleus and prepares the cell to duplicate its DNA (and its centrosomes). As DNA replication continues, cyclin E is destroyed, and the level of mitotic cyclins begins to rise (in G2). Translocation of M-phase promoting factor (the complex of mitotic [B] cyclins with the M-phase Cdk [Cdk1]) into the nucleus initiates assembly of the mitotic spindle
breakdown of the nuclear envelope
cessation of all gene transcription
condensation of the chromosomes
These events take the cell to metaphase of mitosis.
At this point, the M-phase promoting factor activates the anaphase-promoting complex (APC/C) which allows the sister chromatids at the metaphase plate to separate and move to the poles (= anaphase), completing mitosis. Separation of the sister chromatids depends on the breakdown of the cohesin that has been holding them together. It works like this. Cohesin breakdown is caused by a protease called separase (also known as separin). Separase is kept inactive until late metaphase by an inhibitory chaperone called securin. Anaphase begins when the anaphase promoting complex (APC/C) destroys securin (by tagging it with ubiquitin for deposit in a proteasome) thus ending its inhibition of separase and allowing separase to break down cohesin.
destroys B cyclins. This is also done by attaching them to ubiquitin which targets them for destruction by proteasomes. turns on synthesis of G1 cyclins (D) for the next turn of the cycle. degrades geminin, a protein that has kept the freshly-synthesized DNA in S phase from being re-replicated before mitosis. This is only one of the mechanisms by which the cell ensures that every portion of its genome is copied once — and only once — during S phase. Link to discussion.
Some cells deliberately cut the cell cycle short allowing repeated S phases without completing mitosis and/or cytokinesis. This is called endoreplication and is described on a separate page. Link to it. Meiosis and the Cell Cycle
The special behavior of the chromosomes in meiosis I requires some special controls. Nonetheless, passage through the cell cycle in meiosis I (as well as meiosis II, which is essentially a mitotic division) uses many of the same players, e.g., MPF and APC. (In fact, MPF is also called maturation-promoting factor for its role in meiosis I and II of developing oocytes. Checkpoints: Quality Control of the Cell Cycle
The cell has several systems for interrupting the cell cycle if something goes wrong. DNA damage checkpoints. These sense DNA damage both before the cell enters S phase (a G1 checkpoint) as well as after S phase (a G2 checkpoint). Damage to DNA before the cell enters S phase inhibits the action of Cdk2 thus stopping the progression of the cell cycle until the damage can be repaired (with the aid of BRCA2). If the damage is so severe that it cannot be repaired, the cell self-destructs by apoptosis.
Damage to DNA after S phase (the G2 checkpoint), inhibits the action of Cdk1 thus preventing the cell from proceeding from G2 to mitosis. A check on the successful replication of DNA during S phase. If replication stops at any point on the DNA, progress through the cell cycle is halted until the problem is solved. Discussion of DNA replication.
spindle checkpoints. Some of these that have been discovered detect any failure of spindle fibers to attach to kinetochores and arrest the cell in metaphase until all the kinetochores are attached correctly (M checkpoint — example); detect improper alignment of the spindle itself and block cytokinesis; trigger apoptosis if the damage is irreparable.
All the checkpoints examined require the services of a complex of proteins. Mutations in the genes encoding some of these have been associated with cancer; that is, they are oncogenes. This should not be surprising since checkpoint failures allow the cell to continue dividing despite damage to its integrity. Examples
The p53 protein senses DNA damage and can halt progression of the cell cycle in G1 (by blocking the activity of Cdk2). Both copies of the p53 gene must be mutated for this to fail so mutations in p53 are recessive, and p53 qualifies as a tumor suppressor gene.
The p53 protein is also a key player in apoptosis, forcing “bad” cells to commit suicide. So if the cell has only mutant versions of the protein, it can live on — perhaps developing into a cancer. More than half of all human cancers do, in fact, harbor p53 mutations and have no functioning p53 protein. A genetically-engineered adenovirus, called ONYX-015, can only replicate in human cells lacking p53. Thus it infects, replicates, and ultimately kills many types of cancer cells in vitro. Clinical trials are now proceeding to see if injections of ONYX-015 can shrink a variety of types of cancers in human patients. (You will find that the human gene is variously designated as P53, TP53 [“tumor protein 53”], and TRP53 [“transformation-related protein 53”]) ATM
ATM (=”ataxia telangiectasia mutated”) gets its name from a human disease of that name [Link], whose patients — among other things — are at a greatly increased (~100 fold) risk of cancer. The ATM protein is involved in detecting DNA damage, especially double-strand breaks;
interrupting (with the aid of p53) the cell cycle when damage is found; maintaining normal telomere length.
MAD (=”mitotic arrest deficient”) genes (there are two) encode proteins that bind to each kinetochore until a spindle fiber (one microtubule will do) attaches to it. If there is any failure to attach, MAD remains and blocks entry into anaphase (by inhibiting the anaphase-promoting complex). Mutations in MAD produce a defective protein and failure of the checkpoint. The cell finishes mitosis but produces daughter cells with too many or too few chromosomes (aneuploidy). Aneuploidy is one of the hallmarks of cancer cells suggesting that failure of the spindle checkpoint is a major step in the conversion of a normal cell into a cancerous one. Infection with the human T-cell lymphotropic virus-1 (HTLV-1) leads to a cancer (ATL = “adult T-cell leukemia/lymphoma”) in about 5% of its victims. HTLV-1 encodes a protein, called Tax, that binds to MAD protein causing failure of the spindle checkpoint. The leukemic cells in these patients show many chromosome abnormalities including aneuploidy. A kinesin that moves the kinetochore to the end of the spindle fiber also seems to be involved in the spindle checkpoint G0
Many times a cell will leave the cell cycle, temporarily or permanently. It exits the cycle at G1 and enters a stage designated G0 (G zero). A G0 cell is often called “quiescent”, but that is probably more a reflection of the interests of the scientists studying the cell cycle than the cell itself. Many G0 cells are anything but quiescent. They are busy carrying out their functions in the organism. e.g., secretion, attacking pathogens. Often G0 cells are terminally differentiated: they will never reenter the cell cycle but instead will carry out their function in the organism until they die. For other cells, G0 can be followed by reentry into the cell cycle.
Most of the lymphocytes in human blood are in G0. However, with proper stimulation, such as encountering the appropriate antigen they can be stimulated to reenter the cell cycle (at G1) and proceed on to new rounds of alternating S phases and mitosis. G0 represents not simply the absence of signals for mitosis but an active repression of the genes needed for mitosis. Cancer cells cannot enter G0 and are destined to repeat the cell cycle indefinitely.
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is a form of karyokinesis, or nuclear division. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles, and cell membrane into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle—the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle. Mitosis occurs only in eukaryotic cells and the process varies in different species. For example, animals undergo an “open” mitosis, where the nuclear envelope breaks down before the chromosomes separate, while fungi such as Aspergillus nidulans and Saccharomyces cerevisiae (yeast) undergo a “closed” mitosis, where chromosomes divide within an intact cell nucleus. Prokaryotic cells, which lack a nucleus, divide by a process called binary fission.
The process of mitosis is fast and highly complex. The sequence of events is divided into stages corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During mitosis the pairs of chromatids condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells which are still diploid cells. Because cytokinesis usually occurs in conjunction with mitosis, “mitosis” is often used interchangeably with “mitotic phase”. However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei.
This occurs most notably among the fungi and slime moulds, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development. Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to certain types of cancer. Mitosis was discovered in frog, rabbit, and cat cornea cells in 1873 and described for the first time by the Polish histologist Wacław Mayzel in 1875. Meiosis
In sexual reproduction, two parents give rise to an offspring with an unique gene combination from either of them — each parent gives 1/2 of his/her genes to the offspring. A gene is a discrete unit of information on the DNA that codes for one protein, perhaps one of the many enzymes needed by our bodies. Somatic cells have two sets of chromosomes; one set from each parent. For example, in humans one set = 23 chromosomes, so our somatic cells have 46 chromosomes arranged in 23 pairs. The two chromosomes in each pair are referred to as being homologous chromosomes, so we could say that humans have 23 pairs of homologous chromosomes. The two chromosomes of each pair carry genes for the same trait (for example, eye color) at the same location, but not necessarily the same form of that gene (for example, brown vs. blue eyes).
An important exception to this is the sex chromosomes, the X and Y chromosomes. Although these chromosomes pair with each other, they are not the same size. The X-chromosome is longer and has genes for many traits with no match on the Y-chromosome. A person with XX would be female and someone with XY would be male (although, that’s not true of all other organisms). All the other chromosomes are called autosomes. Somatic cells have two sets of autosomes (however many pairs that is) and one pair of sex chromosomes so are called diploid or 2n cells. Thus, humans would have 44 + XX or 44 + XY chromosomes, and fruit flies would have 6 + XX or 6 + XY. Gametes or sex cells (eggs from female and sperm from male) have one chromosome from each autosome pair and one sex chromosome (one set of chromosomes), thus are called haploid or 1n. Human eggs would have 22 + X chromosomes, and human sperm would have 22 + X or 22 + Y chromosomes. Similarly, fruit fly eggs would have 4 + X chromsomes and their sperm would have 3 + X or 3 + Y chromosomes. Meiosis is a special type of cell division that produces gametes with half as many chromosomes.
The opposite process would be syngamy or fertilization, which is the union of the egg and sperm to restore the 2n number. This results in a zygote, the first cell formed by fertilization, a completely new and different organism with unique genetic information different from either parent. The zygote divides and grows to form an embryo which developes into a young organism, then an adult. Life cycles of all sexually-reproducing organisms follow this pattern of alternation of generations. The 2n adult produces 1n gametes by the process of meiosis. These unite in the process of syngamy to produce a new 2n generation. Thus, the life cycles alternate between 1n and 2n stages, and between the processes of meiosis and syngamy. It is because of the way in which genes recombine in meiosis and syngamy that we have the whole study of genetics.
The steps in meiosis are similar to mitosis and even have the same names. However, there is a significant difference in how the chromosomes line up initially. In mitosis, chromosomes line up individually, while in meiosis, the two chromosomes in each homologous pair line up next to each other. This pairing process is called synapsis, and the resulting homologous pair is called a bivalent in reference to the two chromosomes or a tetrad in reference to the four sister chromatids involved. Interphase is the same in both mitosis and meiosis, but in meiosis, it is followed by two cell divisions. These two division processes are referred to as Meiosis I and Meiosis II, and result in a total of four daughter cells, each with a 1n chromosome number.
In prophase I, notice the difference in how the homologous chromosomes behave. They come together and match up (synapsis) in pairs (tetrads or bivalents). In human females, this stage happens prior to birth when the ovaries are forming, and then stops. A baby girl is born with all the precursor egg cells she will ever have in a sort-of “suspended animation” until puberty (hence abdominal x-rays are dangerous for any young to middle-aged human female, not just pregnant women, and hence there is a greater likelihood that a 40-yr-old mother will have a baby with Down Syndrome – due to incorrect meiosis — than a 20-yr-old mother). In metaphase I, the bivalents line up, not individual chromosomes, so there’s a 50:50 chance of which chromosome of each pair faces which pole of the cell. Human “eggs” go about this far through meiosis before they are shed from the ovaries at ovulation. In anaphase I, the homologous chromosomes separate, and one of each pair travels to each of the two poles of the cell, thereby reducing the chromosome number from 2n to 1n. Note that the sister chromatids stay together. Two daughter cells are formed during telophase I. These usually go immediately into the second cell division (meiosis II) to separate the sister chromatids. Meiosis II is pretty much like mitosis, in that the sister chromatids are separated.
This results in four daughter cells, each with an 1n chromosome number. In human females, meiosis II in the precursor egg cells never happens until/if a sperm first enters the egg to fertilize it. Fertilization triggers Meiosis II, and then the sperm nucleus unites with the resulting egg nucleus. Thus, the unfertilized “eggs” that a woman sheds each month are not true eggs. Also in human females, division of the cytoplasm is not even. This provides a way of keeping as much cytoplasm as possible with the future egg/zygote. Rather than equal-sized gametes, one big egg and three smaller polar bodies with minimal cytoplasm are formed. Interestingly, because the homologous pairs line up during Metaphase I, there is a 50:50 chance of which one of each pair will go to each of the poles of the cell (like flipping a coin, where you can get either heads or tails).
Therefore, in humans with 23 pairs of chromosomes, a gamete (egg or sperm) could have 223 or 8,388,604 possible combinations of chromosomes from that parent. Any couple could have 223 × 223 or 70,368,744,177,644 (70 trillion) different possible children, based just on the number of chromosomes, not considering the actual genes on those chromosomes. Thus, the chance of two siblings being exactly identical would be 1 in 70 trillion. In addition, something called crossingover, in which the two homologous chromosomes of a pair exchange equal segments during synapsis in Meiosis I, can add further variation to an individual’s genetic make-up.