Cell+Cycle

The Cell Cycle  Aayushi Mehta, Jess Resnick, Niha Yerneni media type="youtube" key="l88IJoM2aK0" height="315" width="420" align="center"





**Interphase (stage 1):** Interphase is the stage in which the cell in constantly making proteins, RNA and growing in size. This occurs within mammalian tissue cells and lasts anywhere from 12-24 hours. The cell spends most of its time in interphase. Interphase can be divided into 4 phases: G0, G1, S Phase, and G2. No fear; all will be explained!

**G0**, also known as Gap 0, is the phase in which the cell has the first opportunity to leave the cell cycle and stop dividing. A cell can temporarily remain in the G0 phase, or may remain there permanently. An example of a cell remaining in this stage could be a diseased or mutated cell like a cell that could become cancerous is replicated Another example of this is a neuron that has matured as a cell and has no further need to replicate. [[|8]]

**G1**, aka Gap 1, is the next phase in interphase. This is the phase in which the cell grows in size. The growth occurs because the cell is rapidly synthesizing RNA and proteins. The cell cycle control mechanism, the G1 checkpoint, takes place here. This is the point where all of the cell's genetic material is checked to make sure the cell is ready for DNA replication, so mutated genes will not be replicated.

**S Phase**, Synthesis Phase, is where the DNA is completely replicated in order to be used in 2 identical daughter cells to be produced in the M phase (aka the Mitosis phase to be explained later!).

** G2 ,** Gap 2, is a very special phase. Besides having protein synthesis occurring, proteins needed for cell division to occur, G2 is also the phase in which a second checkpoint occurs in the cell. The G2 checkpoint is where the cell's genetic material is checked for the last time before entering mitosis. If a genetic mutation in discovered in the cell's DNA, the cell will be stopped and not enter the M phase, keeping the genetic mutation from being replicated into more cells.[[|8]]



**M Phase (stage 2, the last stage)**, Mitosis Phase, is where protein synthesis and cell growth stop. This is the point in the cell cycle where all of the cell's energy is focused into the formation of two identical daughter cells, when the parent cell will "unzip" its own DNA in two and the halves if the helix will be replaced by the action of proteins produced in earlier parts of the cycle. Mitosis only lasts about 2 hours, far shorter than interphase. There is a checkpoint within mitosis at the Metaphase checkpoint in which the cell is reviewed one last time before its given the go-ahead to complete cell division. Mitosis is broken down into 7 stages: interphase, prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis. **G2 of Interphase** is the stage during which the nuclear envelope bounds the nucleus. The nucleus has one or more nucleoli and two centrosomes form by replication of single centrosome. In animal cells, each centrosome features 2 centrioles. Chromosomes duplicated during S phase cannot be seen yet because they are not condensed yet. [[|8]]

**Prophase** is where chromatin fibers become tightly coiled and condense into chromosomes. During this stage, nucleoli disappears and each duplicated chromosome appears as two identical sister chromatids joined by centromeres along their arms by cohesins. Mitotic spindles, composed of centrosome and microtubules that extend from them, are formed. Radial arrays of shorter microtubules that extend from centrosome are asters. Centrosome moves away from each other propelled by the lengthening of microtubules between them.

**Prometaphase** is the stage where nuclear envelope fragments. Microtubules extending from each centrosome invade nuclear area and each of the two chromatids of each chromosome has kinetochore (specialized protein structure located at centromere). Some microtubules attach to kinetochores and are known as kinetochore microtubules which jerk chromosomes back and forth. Nonkinetochore microtubules interact with those from opposite pole of spindle.

**Metaphase** is the longest stage of mitosis (~ 20 mins). The centrosomes are at opposite poles of cell at this stage. The chromosomes convene on metaphase plate (imaginary plate that is equidistant between spindle's poles) and the chromosomes' centromeres lie on metaphase plate.

**Anaphase** is the shortest stage of mitosis. It begins when cohesin proteins are cleaved, allowing two sister chromatids to suddenly part. Each chromatid becomes a full-fledged chromosome. The two daughter chromosomes move toward opposite ends of cell as kinetochore microtubules shorten. The microtubules are attached at centromere region so chromosomes move the centromere first. The cell elongates as nonkinetochore microtubule lengthens. By the end of anaphase, two ends of the cell have equal and complete chromosomes.

**Telophase** is the stage where two daughter nuclei form. The nuclear envelopes arise from fragments of parent cell's nuclear envelope and other parts of endomembrane system. The nucleoli reappear and the chromosomes are less condensed. Mitosis (decision of one nucleus into 2 genetically identical nuclei) is complete.

**Cytokinesis** is the division of cytoplasm that is usually well underway by late telophase. Two daughter cells appear shortly after end of mitosis. In an animal cell, cytokinesis involves formation of cleavage furrow, which is the pinching of the cell into two parts. [[|6]]

A sentence for the acronym **IPPMATC** to remember these phases in order is: I n P erspective, P andas M ake A T errific C ompanion




 * CDK || Cyclin Partner || Function || Effect ||
 * CDK 1 || Cyclin B || M Phase || None ||
 * CDK 2 || Cyclin E || S Phase || Reduced Size; Sterile & Viable Males+Females ||
 * CDK 2 || Cyclin A || S Phase || Viable & Fertile Males+Females ||
 * CDK 3 || Cyclin C || G1 Phase || No Defects; Viable & Fertile ||
 * CDK 4 || Cyclin D || G1 Phase || Reduced Size, Insulin Deficient Diabetes. Viable & Sterile ||
 * CDK 5 || P53 || Transcription || Severe Neurological Defects; Died After Birth. ||
 * CDK 6 || Cyclin D || G1 Phase || CDK activating ||
 * CDK 7 || Cyclin H |||| Transcription ||
 * CDK 8 || Cyclin C |||| Transcription ||
 * CDK 11 || Cyclin L ||  || Mitosis Defects ||

**Controls** **Cyclin-dependent kinases (CDKs)** are a category of protein kinases. They regulate the cell cycle and are involved in regulating transcription, mRNA processing, and differentiation of nerve cells. They are in all eukaryotes. They bind to a regulatory protein, known as cyclin. Without cyclin, they have little activity. The first CDK found was MPF, also known as Cdk 1. It is imperative that cell division only occur after satisfactory growth and DNA replication, thus the existence of checkpoints allows for coordination and regulation. Acting as enzymes, CDKs phosphorylate their substrates and different cells may have varying numbers and kinds of CDKs. Cyclin comes into play when it binds to a CDK that is in a specific state: with some sites dephosphorylated and others phosphorylated. Effective phosphorylation also depends on other enymes called phosphatases that are required to remove phosphate groups from proteins.

Each CDK is paired with a specific cyclin (which is named by the stage they act in). A few common cyclins are from the phases G1, G1/S, S, and M. The cyclins from the M phase create a M-CDK complex that leads the cell into mitosis. The cell cycle's movement depends on the amount to cyclin available, something that varies by stage. CDK levels by comparison, are relatively stable. The cell synthesizes specific cyclins at different times, for example the G1 and G1/S cyclins are created at two different times during the G1 phase. The cyclin must also be degraded in an organized manner for the cycle to continue; mistakes can cause cell cycle arrest. Degradation is important because then the corresponding CDKs become inactive..

Each CDK-cyclin complex recognizes several substrates, allowing them to coordinate the multiple events of each phase. The M-CDK is a good example, as it affects a range of proteins including condensin and lamin. Condensin is the protein that condenses mitotic chromosomes, and lamin forms a network under the nuclear membrane that comes apart during mitosis. It also regulates microtubules, which in turn affects the building of the mitotic spindle.[[|3]]



The image above explains the controls of the cell cycle in greater detail.

a. The cell goes through three transitions: S-phase is the beginning of DNA replication, M-phase is the nuclear membrane breakdown and the condensation of the chromosomes and between metaphase and anaphase is when the sister chromatids are separated. These transitions are regulated by CDKs.

b. Certain CDKs may bind to several different cyclins, but may prefer one over the other. The black lines show the possible pairings: CDK1 is very versatile, while CDK4 and 5 can only bind with cyclin D. The red lines are the preferred pairings.

c. In the classical model, CDK4 or 6 binds with cyclin D and regulates in early G1, Cyclin E-CDK2 triggers the S phase, the cyclin A-CDK2 and the cyclin A-CDK1 complexes control the end of S phase, and CDK1-cyclin B is responsible for mitosis.

d. In the threshold model, there is a difference between interphase and mitotic CDKs because of varying locales and increased activity levels for mitosis, but not from substrate specificity. CDK1 or 2 with cyclin A is enough for interphase, but cyclin B-CDK1 is necessary to go into mitosis ([|3]).

As stated earlier, the cell has controls within the cell cycle at phases G0, G1, G2. The steps that are taken within these control phases are vital in protection against cell mutations such as cancer. These checkpoints are thus vital to maintaining life. [[|6]]

Internal cell controls act as the breaks in the cell cycle that make sure the cell is ready to proceed with division. By using checkpoint to monitor is genetic material has undergone a change or mutation. When mutations or damage occurs to the genome, the cellular instructions, the blueprint of the cell is changed. Controls make sure these changes do not occur and thus do not affect the resultant chromosomes formed by the cell.

Controls use proteins and enzymes to run-over the chromosomes of cells to make sure the genetic material divided by a previous cell cycle has not had genetic mutations, such as point mutations where one of the nucleotide bases has not been deleted (all guanines, cytosines, adenine, and thymines are present). Other errors the controls check for are deletion of complete genes or the addition or copying of genes. [[|7]]

The checkpoint proteins are used to unwind the double helix which is the DNA strand. The protein specific for unwinding is called helicase. Checkpoint proteins make sure mutations don’t occur in chromosome formation which can lead to the uneven distribution of chromosomes into daughter cells which will thus be not identical and faulty. [[|9]]

Controls within the cell are also used to repair cell mutations. Some proteins are able to scan over the DNA and if detecting a point mutation in which a nucleotide base is missing, proteins can replace that missing base and save the genetic material. [[|9]]

If control proteins sense a mutation, DNA polymerase is inhibited keeping DNA replication at bay. When DNA polymerase is not controlled is a sign that a cell has become cancerous.

Controls occurring from stimuli outside the cell include inhibitory growth stimuli signals sent out by normal cells surrounding a cell. These signals, if in great amounts will make a cell stop dividing. This is a control against unstoppable cell growth if a cell is not stimulated to reproduce if the right amount of cell already exists in one area. When a cell divides without the ability to respond to this outside stimuli control, this is a sign that the cell has become cancerous and has mutated beyond cellular controls. Some of these growth factors are proteins released in cells like PDGF (platelet derived growth factor) and EGF (epidermal growth factor). EGF receptors like Her-2 are what bind proteins that stimulate growth and bind them to the cell's proliferation pathway.

Controls that can inhibit these receptors are an external control against proliferating cells with genetic mutated material. Guanosine diphosphate (GDP) is a molecule necessary for controlling the signaling pathways in living cells. GDP is formed when a phosphate group is removed from GTP, guanine triphosphate. GTP is used often in the cell to power cellular activities by losing their phosphate group and releasing energy.

Fos and Jun proteins, proteins responsible for DNA transcription, which are heavily monitored by control proteins to monitor transcription, when mutated show they often yield to cancer. This is because the controlled process of DNA transcription leads to the correct amino acid sequences is yielded and the correct proteins being made. Proteins not only are responsible for acting as controls for cellular replication, but also the foundation for all cellular action to occur (besides the genetic material used to create the proteins themselves). Without these proteins, the cell is lost to faulty replication and cellular action. [[|7]] [|10]

Cancer suppressing proto-oncogenes, such as Ras protein, will sets up checkpoints in all the stages of the cell cycle (besides G0, which is in itself is a checkpoint and holding ground for cells in cell arrest). Ras checks genetic material at the end of G1, the middle of S phase, at the end of G2, and in the middle of M phase [[|10]]

**Telomeres**

Telomeres are structures found at the end of chromosomes which play an essential role in stabilizing these ends. They contain an array of highly repeated DNA sequences and specific binding proteins. Telomeres keep the chromosomes protected and stop them from fusing into rings or binding with other DNA. [ [|1] ] In cell division, when the chromosome "breaks" between two daughter cells, the end of the chromosome is capped off by a telomere by the action of the enzyme telomerase. Telomeres consist of a 6-8 base-pair long sequence that is repeated thousands of times, forming a funky loop at the end of the chromosome. These loops are called T-loops and are capped off by binding proteins.

Telomeres are vital because they protect the chromosomes from being bound with foreign molecules that can cause mutations in the genetic material and appear to have the same function in all species. Telomeres shorten faster, causing premature aging when under stress [ [|2] ]. Current research is investigating how to regulate telomere creation and thus discover more about cancer and aging. 5

Here's a great video to wrap up what you have read: media type="youtube" key="2aVnN4RePyI" width="425" height="350"

**Questions**

1. CDK is dependent on ___ a) The cell cycle phase it is involved in b) The side affects c) Its cyclin partner d) All of the above e) None of the above

2. If a cell has 24 chromosomes, how many will it have at the end of mitosis? a) 6 b) 12 c) 24 d) 48 e) Depends on the species

3. All of the following are true of mitosis EXCEPT a) There are 7 phases b) The longest phase is prophase c) Anaphase is the shortest phase d) Cytokinesis is the last phase e) Chromosomes are not viewable in G2 of interphase

4. In which of the stages of the cell cycle checks the cell's genetic material before cell division and replication is allowed to occur? a) G0 b) G1 c) S Phase d) G2 e) M Phase

5. Which stages of the cell cycle are most critical to the genetic material being checked? a) G0, G1, G2 b) G0, G1, G2, S Phase c) S Phase and interphase d) G0, G1, G2, M Phase e) genetic material is checked in every stage of the cell cycle

6. Which of the the following statements about telomeres are true? I. Telomeres form T-loops at the end of chromosomes II. Telomeres only appear in the chromosomes of humans III. Telomeres main function is the protect genetic material a) I only b) II only c) III only d) I and III e) I, II, and III

7. At what stage are most cells in at a given time? a) Prophase b) Interphase c) Anaphase d) Synthesis Phase e) G0 Phase

8. All of the following are true about telomeres except a) They are affected by stress b) Cancer cells produce more telomerase c) It is related to aging d) B and C are true e) A, B, and C are true

9. The nuclear envelope decays at which stage? a) Prophase b) Prometaphase c) Metaphase d) Anaphase e) Telophase

10. All of the following are true in controls EXCEPT: a) Pinpoint mutations can occur b) Occur in G0, G1, G2 c) Blueprint of cell changes d) Use proteins and enzymes e) They can be affected by external stimuli


 * Essay Question: **

The cell cycle outlines the life of each living cell in every organism. a. Explain the phases of the cell cycle that one cell would have to go through. b. Mitosis is cell division. What are the steps involved to create new cells? c. Without regulation and coordination, the cell cycle degrades into disorganized chaos that can lead to illnesses such as Cancer. Explain external, internal, and control by CDKs.

**Annotated Links**

1. [|Telomeres and Aging] 2. [|Telomeres and Stress] 3. [|CDK] 4. [|CDK-Cyclin-Protein binding] 5. Telomere Info 6. [|Cell Cycle Info] 7. [|Control Info Referring to Cancer] 8. [|More information about the Cell Cycle] 9. [|Information about Genetic Material During Mitosis] 10. [|Article about Cell Cycle Controls] 11. [|Cell Cycle Comic Strip]