2009 Group 5 Project
The Cell Cycle
German Pathologist, Rudolf Ludwig Karl Virchow’s realization in 1885 that "cells only arise from pre-existing cells" sparked the beginning of an intense investigation into the cell cycle, which is still as active and dynamic today.  Over the years, a great number of discoveries and advances have been made in bettering our understanding of this cycle.
Early scientists described the cytology of the cell division  and more recently, scientists from an array of disciplines, spanning embryologists to microbiologists have collaborated and begun to understand the underlining mechanisms and workings involved in the cell cycle. 
The Cell Cycle
The cell cycle is a series of changes a cell undergoes from the time it forms until it reproduces itself.  Depending on what text you read, this cycle can be divided into two or four major phases. We will be discussing the division as four phases, as the prescribed text; Essentials in Cell Biology: 2nd Ed.  defines.
- Gap 1 phase (G1)
- Synthetic phase (S phase)
- Gap 2 phase (G2) and
- Mitotic phase (M phase) (see Figure 1).
It is important to understand that the timing, or length, of the cell cycle differs from cell to cell and from organism to organism. For instance, a small single celled organism can quickly reproduce, whereas a more complex multicelluar organism takes longer.  From here on in, we will be discussing the phases of the cycle for that of a typical fast dividing mammalian cell, with an approximate cell cycle of twenty-four hours. 
Gap 1 Phase (G1)
G1 is the interval between the completion of the M phase and the beginning of the S phase.  It is typically the longest and most variable phase of the cell cycle (see Figure 2).
In part, this lengthy time frame can be explained by the fact that G1 ensues the M phase, a phase in which cell division takes place.  The first opportunity for newly formed cells from the M phase to grow and develop is in G1, a phase of rest and growth. In addition to this function, G1 (along with the other gap phase G2) provides a time for cells to monitor their surrounding environment, both inside and outside of the cell, to ensure that conditions are appropriate and preparations are complete before committing to the next phase, the S phase. 
There is another sub phase within the G1 phase, known as the Gap zero phase (G0) (see Figure 3). When conditions are unfavorable, cells delay progress through G1 and enters G0. In this specialized phase, cells can remain in a rest form of periods from days to even years,  before returning to a proliferating state.
Some cells, such as cardiac muscle cells and nerves cells are unable to divide. That is, they have lost their ability to replicate themselves and as a consequence never leave G0 . Other cells like the red blood cells are continually dividing throughout our life. Some cells will only divide under certain circumstance, for instance if part of the cell population is damaged or dies.
The synthetic phase or S phase of the cell cycle occurs between the gap phases of the cycle.  It is a short phase consisting of few hours in which the entire nuclear content of the cell is replicated.  Replication of a DNA molecule is undertaken in 3 steps; where a bidierectional mechanism is initiated to facilitate multiple replication sites along a chromosome. This is subsequent to a preparation period where all hereditary material of the parent DNA molecule is portioned prior to cellular division.  A parent chromosome is composed of 2 complementary strands of DNA, where every base on 1 strand is paired with a specific partner. That is, Adenine (A) pairs with Thymine(T); Guanine(G) pairs with Cytosine(C). 
- The initial step of DNA replication in vertebrate cells involves the unzipping of the 2 strands of DNA, where hydrogen bonds linking base pairs are broken (Navas,etl 1995).
- This leads to new nucleotides binding to the exposed bases as a result of the presence of the DNA polymerase enzyme. Each strand is then used as a template for determining the order of base pairs in the new complementary strand. The resulting strand is complementary to the pre-existing template strand.
- The final step of replication and synthesis produces 1 parent and 1 new strand of DNA (Lakesly, 1989).
At this point the cycle progresses into a phase of rapid protein synthesis to ensure cellular growth.
Different cyclin-dependent kinase complexes trigger the process of DNA synthesis (Moore, 2003). There are 3 main trigger complexes of the S phase, which are classified into a group known as the S phase promoting factors (SPF). There is firstly an accumulation of cyclin E/cdk2 during late G1 phase, initiating the S phase (Dulic, etl. 1992). Cyclin B/cdk2 is synthesised, but phosphorylation of the complex occurs at Thr14 -Tyr15 and renders it inactive. Lastly, cyclin A/cdk2 (which is considered the most prominant factor in the group) enters the cell nucleus and lead to preparation for cellular duplication it accumulates during S phase and its activation triggers the transition to G2 of the cycle (Reis et al., 2005).
Gap 2 Phase (G2)
The G2 phase of the cell cycle is the third stage of the cell cycle, preparing the cell for entry into mitosis (M phase). It is the second shortest phase of the cell cycle after mitosis, lasting approximately four to five hours in a 24-hour cell cycle (Copper & Hausman, 2006). It is a period of rapid cell growth and production of new proteins, similar to G1 and includes key mechanisms that control the completion of DNA and chromosomal replication following DNA synthesis during the S phase (Pardee, Dubrow, Hamlin & Kletzien, 1978).
In G2, the nucleus bound by a nuclear envelope is well defined, and includes at least one nucleolus. However, the replicated chromosomes occur as loosely packed chromatin fibres and cannot be distinguished individually (Bell & Dutta, 2002). One key process that occurs during G2 is the duplication of the centrosomes resulting with two centrosomes by the end of G2 (Pardee et al., 1978). This centrosome replication is necessary in order to guide the chromosomes during the M phase that follows.
Cyclins and cyclin dependent kinases (CDKs) are a family of proteins which regulate the distinct stages of the cell cycle (Israels & Israels, 2000). During the G2 phase, cyclins A and B coupled to CDK-1 drives the cell up to the M phase (Johnson & Walker, 1999).
The successful transition from G2 to the M phase is controlled by a key checkpoint at the end of this gap phase. This ‘DNA structure checkpoint’ has the important role of providing a quality check ahead of mitosis (Hartwell & Weinert, 1989). If DNA replication is incomplete or if there are mistakes in the copies of DNA, the G2 checkpoint prevents the transition to M phase and cells will undergo repair or apoptosis (programmed cell death) (Kaufmann & Paules, 1996). p53 is a protein which can block the cell cycle if the DNA is damaged. By blocking the cell cycle, it provides more time for DNA repair and increased p53 levels are present in damaged cells (Taylor & Stark, 2001).
Mitosis can be divided into five key stages. These stages are prophase, prometaphase, metaphase, anaphase and telophase.
The prophase stage is signified when the DNA has been replicated and the resulting chromosomes become condensed. Each chromosome is made up of of two chromatids, these pairs of chromatids are linked by a structure called the centromere (Germann & Stanfield, 2005). The centrioles also start moving to opposite poles of the cell allowing the mitotic spindle to develop in between. Microtubules disassemble into their tubulin components which will be used to form the mitotic spindle (Germann & Stanfield, 2005).
As the nuclear envelope deteriorates the cell enters the prometaphase stage whereby the centrioles have completed moving to opposite poles of the cell and the chromosomes attach to the spindle fibres via the kinetochores located at the centromere (Germann & Stanfield, 2005).
Once the chromosomes have completely bound to the spindle fibres, the chromosomes align to the metaphase plate located at the centre of the cell, signalling that the cell is at metaphase (Germann & Stanfield, 2005).
Following metaphase, anaphase is characterised by the separation of the chromatid pairs, with the chromosomes moving towards opposite poles of the cell as they follow along the mitotic spindle. This chromosomal movement and separation is referred to as anaphase A, while the separation of the spindle poles is called anaphase B (Germann & Stanfield, 2005).
The final stage of mitosis is telophase whereby new nuclear envelopes develop on both sides of the cell, with the chromosomes beginning to decondense into chromatin, the breakdown of the mitotic spindle also begins. Also during this time the mother cell is completely divided creating two daughter cells by the process of cytokinesis. These daughter cells then enter interphase at G0, restarting the cell cycle (Germann & Stanfield, 2005).
Progression through the cell cycle is monitored at various checkpoints, where inhibition or activation of the cell cycle is possible depending on cyclin/cdk binding activity (Morgan D, 2007). In the cell cycle 3 major checkpoints are elicited, these include:
1. G1/S checkpoint (restriction point)
2. G2/M checkpoint
3. M-phase checkpoint.
1. The first checkpoint is theG1 checkpoint (also known as the restriction point) occurs midway through the cell cycle's G1 phase. At this point the cell accesses whether it should divide, delay division, or entre a resting period (G0). The restriction point is mainly controlled by the actions of Cdk inhibitors (Elledge, 1996; Johnson & Walker, 1999).
Activation at the restriction point is a result of appropriate cyclin-cdk complex forming and will trigger the phosphorylation of proteins, which in tern activates M-phase cyclins, thereby leading to the transition into G2/M checkpoint. Conversely should an error occur during DNA replication G1/S cyclin-cdk complexes (at the restriction point) will not bind and hence inhibition of cycle progression to G2/M checkpoint will occur.(Morgan D, 2007)
2. What takes place at the G2 checkpoint?
- The cell is checked to make sure that DNA is replicated successfully and that two identical sets of the genome are now present and intact (Elledge, 1996).
- Proof reading of both sets of the genome takes place and a check for molecular damage decides on whether the genome will be maintained, repaired or rejected (Shackelford, Kaufmann & Paules, 1999).
- If DNA repair is required, the cell cycle is delayed for the duration of the DNA repair.
- If DNA is badly damaged and rejected, apoptosis (programmed cell death) will be triggered.
- Overall competence of the cell to enter mitosis is determined. If the cell is ready, mitosis promoting factor (MPF) promotes the entrance into mitosis (Hartwell & Weinert, 1989).
3. At the M-phase checkpoint…
Presence of checkpoints in the cell cycle ensure duplication of genomic material occurs without error such that abnormalities resulting from genomic instability can be avoided (Elledge,1996).
When a cell starts dividing uncontrollably, producing more and more cells, which also divide uncontrollably, it eventually produces a mass of cell, known as a tumor. The tumor might them begin to interfere with normal body functions causing disease. Although not fully understood, it is thought that a tumor is the result of an abnormal regulation of the cell cycle.
Cellular abnormalities may also be a result of errors incurred during DNA replication wherein discrepancies in nucleotide sequences of the chromosome may be found. Such errors within a genome have the potential to cause cellular malfunctioning and mutation of the gene. Accumulation of mutated genetic material leads to the development of cancer.
Historic Timeline of the Cell Cycle
- Link to a Nature article 'Cell Division Milestones' Gives a detailed description of the historic findings of the cell cycle.
- In the 1950s structure of DNA was identified as well as the process of DNA replication
- In the 1980s cell cycle regulators were identified, such as cyclins and Cdks.
- Current research is now centred around the versatiliy of a master control protein kinase and its effects in preventing further cycles of DNA synthesis
- Alberts B, Bray D, Hopkin K, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Essentials in Cell Biology: 2nd Edition. Garland Science Textbooks. 2004.
- Singer S. A Short History of Biology. Clarendon, Oxford. 1931.
- Boye E, Nordström K. Coupling the cell cycle to cell growth. EMBO Rep. 2003 Aug;4(8):757-60. PMID 12897798
- Tanaka S, Nojima H. Nik1: a Nim1-like protein kinase of S. cerevisiae interacts with the Cdc28 complex and regulates cell cycle progression. Genes Cells. 1996 Oct;1(10):905-21. PMID 9077450
- Foundation N. The Cell Cycle Development. WileyBlackwell. 2001.
- Copper GM, Hausman RE. The Cell: A Molecular Approach, 4th Ed. 2006 ASM Press and Sinauer Associates, Inc. 2006.
- Smith JA, Martin L. Do cells cycle? Proc Natl Acad Sci U S A. 1973 Apr;70(4):1263-7. PMID 4515625
- Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science. 1989 Nov 3;246(4930):629-34. PMID 2683079
- Laskey RA, Fairman MP, Blow JJ. S phase of the cell cycle. Science. 1989 Nov 3;246(4930):609-14 PMID 2683076
- Moore JD, Kirk JA, Hunt T. Unmasking the S-phase-promoting potential of cyclin B1. Science. 2003 May 9;300(5621):987-90. PMID 12738867
- Reis VC, Torres FA, Poças-Fonseca MJ, De-Souza MT, Souza DP, Almeida JR, Marinho-Silva C, Parachin NS, Dantas Ada S, Mello-de-Sousa TM, Moraes LM. Cell cycle, DNA replication, repair, and recombination in the dimorphic human pathogenic fungus Paracoccidioides brasiliensis. Genet Mol Res. 2005 Jun 30;4(2):232-50. PMID 16110444
- Alberts, B., Bray, D., Hopkin, K., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2003). Essentials in Cell Biology, 2nd ed. Garland Science Textbooks.
- Bell, S. P., & Dutta, A. (2002). DNA replication in eukaryotic cells. Annual Review of Biochemistry., 71, 333-374.
- Boye, E., & Nordstrom, K. (2003). Coupling the cell cycle to cell growth: A look at the parameters that regulate cell-cycle events. Embryology Reports 4, 8, 757–760.
- Copper, G. M., & Hausman, R. E. (2006). The Cell: A Molecular Approach, 4th ed. 2006 ASM Press and Sinauer Associates, Inc.
- Dulic, V., E. Lees, and S. I. Reed. 1992. Association of human cyclin E with a periodic G1-S phase protein kinase. Science 257:1958-1961
- Elledge SJ. Cell cycle checkpoints: Preventing an identity crisis. Science. 1996 Dec;274(5293):1664-1672.
- Foundation, N. (2001). The Cell Cycle Development. WileyBlackwell.
- Germann, W. J., & Stanfiled, C. L. (2005). Principles of Human Physiology, 2nd ed. San Francisco: Pearson Education.
- Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science. 1989;246(4930):629-634.
- Israels ED, Israels LG. The cell cycle. Oncologist. 2000 Dec;5(6):510-3. PMID11110604
- Johnson DG, Walker CL. Cyclins and cell cycle checkpoints. Annual Review of Pharmacology and Toxicology. 1999;39:295-312.
- Kaufmann WK, Paules RS. DNA damage and cell cycle checkpoints. FASEB Journal. 1996 Feb;10(2):238-47. PMID8641557
- Moore JD, Kirk JA, Hunt T. Unmasking the S-phase - promoting potential of cyclin B1. Science. 2003 May;300(5621):987.
- Navas, T.A., Zhou, Z., and Elledge, S.J. (1995). DNA polymerase epsilon links
the DNA replication machinery to the S phase checkpoint. Cell 80, 29–39.
- Nojima, H., & Tanaka, S. (1996). Nik1: a Nim1-like protein kinase of S. cerevisiae interacts with the Cdc28 complex and regulates cell cycle progression. Genes Cells 1, 905-921.
- O’Connell MJ, Walworth NC, Carr AM. The G2-phase DNA-damage checkpoint. Trends in Cell Biology. 2000;10(7):296-303.
- Pardee, A. B. (1989). G1 events and regulation of cell proliferation. Science 246, 603–608.
- Pardee AB, Dubrow R, Hamlin JL, Kletzien RF. Animal cell cycle. Annual Review of Biochemistry. 1978;47:715-750.
- Reis VCB, Torres FAG, Poças-Fonseca MJ, De-Souza MT, et al. (2005). Cell cycle, DNA replication, repair,
and recombination in the dimorphic human pathogenic fungus Paracoccidioides brasiliensis. Genet. Mol. Res. 4: 232-250
- Shackelford RE, Kaufmann WK, Paules RS. Cell cycle control, checkpoint mechanisms, and genotoxic stress. Environmental Health Perspectives. 1999;107(1): 5-24.
- Sherr CJ. Cancer cell cycles. Science. 1996;274:1672-1677.
- Sherr, C. J. (1994). G1 phase progression: cycling on cue. Cell 79, 551-555.
- Singer, S. (1931). A Short History of Biology. Clarendon, Oxford.
- Smith JA, Martin L. Do cells cycle? Proceedings of the National Academy of Sciences. 1973 Apr;70(4):1263-1267.
- Taylor WR, Stark GR. Regulation of the G2/M transition by p53. Oncogene. 2001 Apr;20(15):1803-1815.
- Allocate sections to group members (See above)
- Research topic and headings
- Write and format Wiki
- Citation and reference
- Use 'edit' and 'discussion' to make comments/ explanations
- Review and edit project page as allocated
- Monitor and review all the edits
- Write group reflection
- Download all the edits made during the 'edit' period
- Submit final wiki version by WEDNESDAY
2009 Group Projects
--Mark Hill 14:02, 19 March 2009 (EST) Please leave these links to all group projects at the bottom of your project page.
Group 1 Meiosis | Group 2 Cell Death - Apoptosis | Group 3 Cell Division | Group 4 Trk Receptors | Group 5 The Cell Cycle | Group 6 Golgi Apparatus | Group 7 Mitochondria | Group 8 Cell Death - Necrosis | Group 9 Nucleus | Group 10 Cell Shape