Cell division is the process of formation of two or more daughter cells from a parent cell’s division. Its occurrence leads to growth and reproduction in organisms. The division of cells must be such that the increase in cell mass and duplication of the genetic material results in each progeny with equal complement of genetic material to ensure continuation of the cell line. Thus, this is carried out in an orderly fashion in a call’s life span and is termed as CELL CYCLE. Cell division usually occurs as part of a larger cell cycle. Initially, a diploid cell with 2n chromosomes will undergo a growth period and its cell mass will increase; this denotes the G1 Phase. If a complete cell cycle is calculated in 24 hours, then G1 phase takes 10 hours of that period where the cell continues to grow and chemical preparation of DNA synthesis takes place. The G1 Checkpoint makes sure the cell is ready to proceed to the next phase.
The next is S Phase wherein, the genetic material of every chromosome is replicated in about 9 hrs. Once the replication is complete, the cell enters G2 Phase. About 4 hours long, this phase is necessary for continued growth and the G2 Checkpoint ensures whether the cell meets all the requirements to proceed to the M phase of cell cycle. In M Phase, cell growth stops and cellular energy is centered at successful division of cell into progenies. It possesses a Metaphase Checkpoint in the middle of mitosis to ensure that the cell is ready to complete cell division. The G1, S and G2 phases are collectively called Interphase which is followed by Mitosis Phase.
Cell cycle starts with a G0 Phase or Resting Phase where the cell goes out of the cycle and stops division. Non-proliferative and fully differentiated cells stay in this phase almost indefinitely (neurons) or semi-permanently (Eg.: liver, and kidney cells). Eukaryotes have two distinct types of cell division: a vegetative division, where each daughter cell is a genetic clone of its parent (MITOSIS), and a reproductive cell division, where the chromosome number in daughter cells is reduced by half to produce haploid gametes (MEIOSIS). Meiosis causes formation of four haploid daughter cells through one cycle of DNA replication and two cell divisions. 1st division separates Homologous chromosomes while the 2nd division separates the Sister chromatids.
Prokaryotes namely bacteria undergo binary fission where their genetic material gets equally segregated into two daughter cells. Other forms of vegetative cell divisions include budding, fragmentation etc. Cell division, regardless of the organism, is preceded by a one round of DNA replication. Mitotic cell division is needed for reproduction, growth, repair and maintenance of the cell’s genome . The human body experiences about 10 quadrillion cell divisions in a lifetime. Thus it is evident that without the cell cycle, life cannot continue. Hence it only natural, that a vast network of regulatory mechanisms control this complex system.
Interphase implies a preparatory stage of changes in a new cell which make it capable of dividing yet again. This is where the cell spends 91% of its life span 4. As mentioned before, interphase constitutes 3 stages of G1, S, and G2 which is then followed by the cycle of mitosis and cytokinesis.
G1 Phase (Gap1 Phase)
This is the first growth phase or the gap phase which proceeds from the culmination of previous cycle’s M phase until DNA synthesis. The key features of this phase include: –
a. Resumption of biosynthetic activity at a faster pace post M phase.
b. Increase in number of proteins.
c. Increase in number of organelles like mitochondria, ribosomes etc.
d. Increase in cellular size.
In G1 phase, a cell is presented with three options. These are: –
a. Continue with the cell cycle and enter the S phase.
b. Discontinue from the cycle and enter G0 phase for differentiation.
c. Stop semi-permanently in G1, and either enter G0 or re-enter the cycle.
S Phase (Synthesis Phase)
DNA synthesis in the cell marks the beginning of this phase. Its completion is marked by the total replication of each chromosome into their respective 2 sister chromatids. The S phase constitutes certain key features which are as follows: –
a. Doubling of total DNA in the cell while the ploidy remains the same.
b. Slow rate of RNA transcription
c. Reduced protein synthesis although histone protein is produced abundantly.
G2 Phase (Gap2 Phase)
Following the completion of DNA replication, the cell enter G2 phase
where the following changes occur: –
a. Rapid synthesis of proteins
b. Rapid cell growth in preparation for mitosis
c. Formation of spindles by reorganization of microtubules.
As mentioned earlier, there are checkpoints after each phase that control the progression of the cell in the cycle. These checkpoints are regulated by cyclins and cyclin dependent kinases (CDK). As cyclins increase, cell progresses further into interphase; increased cyclins increase CDK attachment to cyclins until it reaches its peak and causes the cell to move out of interphase and into M-phase. This is where mitosis, meiosis and cytokinesis occurs.
In prophase the following changes occur: –
- The nuclear envelope is broken down.
- Long strands of chromatin condense to form shorter more visible strands called chromosomes.
- The nucleolus disappears.
- Microtubules (spindle fibers) attach to the chromosomes at the kinetochores present in the centromere.
- In MEIOSIS, the homologous chromosomes break from their double-stranded DNA at the same locations, followed by a recombination of the now fragmented parental DNA strands into non-parental combinations, known as crossing over takes place. It is caused by the highly conserved Spo11 protein.
- The centromeres of the chromosomes assemble on the metaphase plate or equatorial plate, which is equidistant from the two centrosome poles and held together by cohesins.
- Chromosomes align due to microtubule organizing centres (MTOCs) by pushing and pulling on centromeres causing the chromosome to move to the centre.
- Chromosomes are still condensing and the spindle fibres have already connected to the kinetochores.
- The chromosomes are ready to split into opposite poles of the cell towards the spindle to which they are connected.
- Anaphase is a brief stage and occurs after chromosomes align at the mitotic plate.
- Kinetochores emit anaphase-inhibition signals until the final chromosome attaches to the mitotic spindle which subsequently triggers the abrupt shift to anaphase.
- The shift is due to activation of the anaphase-promoting complex which tags degradation of proteins important towards the metaphase-anaphase transition.
- One of these proteins, is securin which through its breakdown releases the enzyme separase that cleaves cohesin rings that hold together the sister chromatids and cause chromosome separation.
- Following line up, the spindle fibres will pull them apart. The chromosomes are split and the sister chromatids move to opposite poles.
- As the sister chromatids are being pulled apart, the cell and plasma get elongated by non-kinetochore microtubules.
- It is the last stage of the cell cycle where a cleavage furrow splits the cells cytoplasm (cytokinesis) and chromatin.
- Synthesis of a new nuclear envelopes around the chromatin gathered at each pole.
- Reformation of the nucleolus as the chromosomes de-condense their chromatin back to the loose state it possessed during interphase.
- The division of the cellular contents is not always equal and can vary by cell type (oocyte formation where one of the four daughter cells possesses majority of the cytoplasm).
- It is the last stage of the cell division where cytoplasmic division occurs at the end of either mitosis or meiosis.
- Irreversible separation of cytoplasm leading to two daughter cells. If the division is asymmetric, the daughter cells would be unequal with an excess or depleted reservoir of fate determining molecules.
Molecular Mechanism of Regulation
The mechanism of regulation in required for the survival of the cell. This includes detection and subsequent repair of any genetic damage and prevents unchecked proliferation. These processes are sequenced and directional and are impossible to reverse.
Cyclins and Cyclin Dependent Kinases (CDKs)
They comprise two classes of regulatory molecules, which as highlighted before, control the cell’s progression into the cycle. All eukaryotes have conserved sequences for these two molecules although complex organisms have an elaborate system of regulatory molecules other that these two. Several genes were identified through study of Saccharomyces cerevisiae and named as cell cycle division or cdc.
Cyclins are regulatory subunits which have no catalytic activity of their own while CDKs are the catalytic subunits belonging to an activated heterodimer that can’t be active without a cyclin. When bound to cyclin, CDKs are activated and cause phosphorylation. This process may either activate or inactivate proteins to control the cell’s progression. Various combinations of these molecules are responsible for activating different proteins and downstream processes. CDKs get expressed on the basis of need wherever cyclins get synthesised at particular stages.
a. Mechanism of Action
When the cell receives a pro-mitotic extracellular signal, following changes occur: –
- G1 cyclin-CDK complex is activated. It prepares cell to enter S phase by promoting expression of transcription factors.
- This promotes expression of S-cyclins and of enzymes which are required for DNA replication.
- The G1 cyclin-CDK complexes also promote the degradation of S phase inhibitors by targeting them for ubiquitination (An enzymatic post-translational modification where ubiquitin protein is attached to substrate protein).
- This ubiquitinated protein undergoes proteolytic degradation by the proteasome.
- It has also been recently speculated that cyclins, especially D-CDK4/6 takes part in controlling the timing of cell cycle rather that the progression itself.
- Activated S cyclin-CDK complexes phosphorylate proteins that constitute pre-replication complexes that are assembled during G1 phase on the origins of DNA replication.
- This phosphorylation activates each previously-assembled prereplication complex and prevents new complexes from forming. This ensures that every part of the cell’s genome gets replicated only once.
- Mistakes in this process leads to gaps or formation of extra copies of genes, both of which lead to the death of the daughter cells.
- The cyclin-CDK complexes that were synthesised during S and G2 phases and inactivated, promote initiation of mitosis through stimulation of downstream proteins which are involved in chromosome condensation and mitotic spindle assembly.
- Ubiquitin ligase or the anaphase-promoting complex (APC) gets activated here, which promotes degradation of structural proteins that are associated with the chromosomal kinetochore.
- APC targets the mitotic cyclins for degradation, thus ensuring that telophase and cytokinesis may proceed further.
b. Action of cyclin-CDK complexes
- Cyclin D is the 1st to be activated on receiving an extracellular signal (growth factors, hormones etc.). Its levels stay low in the non-proliferating resting cells.
- CDK4/6 and CDK2 are also inactive since CDK4/6 are bound by INK4 (Inhibitors of CDK4) family members such as p16, which limits their kinase activity.
- CDK2 complexes are inhibited by the CIP/KIP proteins such as p21 and p27.
- When the times arrives for the cell to enter the cell cycle, a trigger provided by mitogenic stimuli, cyclin D concentration increase.
- Thus, cyclin D binds to existing CDK4/6, which forms the active cyclin D-CDK4/6 complex. This formed complex, monophosphorylates the retinoblastoma susceptibility protein (Rb) to pRb (phosphorylated Rb).
- The un-phosphorylated Rb tumour suppressor protein’s main function is to induce cell cycle exit and maintain G0 arrest or senescence.
- This Rb has 3 isoforms, namely: (1) Un-phosphorylated Rb in G0 state; (2) Mono-phosphorylated Rb or hypo-phosphorylated Rb in early G1 state; and (3) Inactive hyper-phosphorylated Rb in late G1 state.
- The several isoforms of mono-phosphorylated Rb have distinct binding affinity to E2F (encodes for family of transcription factors). This results in various specific transcriptional outputs.
- When pRb binds to E2F, it inhibits E2F target gene expression of few G1/S and S transition genes including E-type cyclins.
- The partial phosphorylation of Rb causes Rb-mediated suppression of E2F target gene expression to reduce thus initiating the expression of cyclin E.
- With the steady increase in cyclin E, cyclin E-CDK2 complex activates and hyper-phosphorylates Rb, thereby inactivating it. This Rb then dissociates from E2F/DP1/Rb complex which is bound to E2F which causes enhanced expression of free E2F target genes that proceed the cell into S phase.
- Of all the cyclins present, cyclin D has special affinity to Rb and wherein, upon mutation of Cyclin D-CDK4/6 specific Rb C-terminal helix leads to cell arrest in G1 and reduces tumour suppressing function of Rb.
- Cyclin-CDK mechanism controls the commitment of cells to the cell cycle and its proof is seen in cancerous proliferation where this mechanism’s activity is often deregulated.
- As stated above, E2F activation not only prompts S phase entry, but also causes transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc.
- Activated Cyclin E binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase. This push also initiates the transition of G2/M.
- Cyclin B-CDK1 complex activation causes breakdown of nuclear envelope, initiation of prophase. Its deactivation causes the cell to exit mitosis.
- Genes like Myc regulate the level of E2F accumulation and determines commitment in cell cycle and S phase entry.
- G1 cyclin-CDK activities control the timing of E2F increase and hence regulate pace of cell cycle progression.
These are of two types:-
- The cip/kip family (CDK interacting protein/Kinase inhibitory protein) and the INK4a/ARF family (Inhibitor of Kinase 4/Alternative Reading Frame) play a pivotal role in preventing the progression of the cell cycle.
- As uncontrolled proliferation leads to tumour formation, these genes are also called tumour suppressors.
- The cip/kip family includes p21, p27 and p57 genes. They stop cell cycle in G1 phase through inactivation by binding to cyclin-CDK complexes.
- The p21 is activated by p53 (p53 is triggered by DNA damage e.g. due to radiation) while p27 is activated by Transforming Growth Factor of β (TGF β), a growth inhibitor.
- The INK4a/ARF family includes p16INK4a and p14ARF. The p16INK4a binds to CDK4 and causes the cell to arrest at G1 phase while p14ARF aids in prevention of p53 degradation.
- Synthetic inhibitors of Cdc25 may act as antineoplastic and anti-cancer agents due to their ability to arrest cell cycle.
- Inhibition of CDK 4/6 must prevent progression of tumour and thus its synthetic versions like palbociclib, ribociclib, and abemaciclib have been prepared. However, only those cancers where Rb (retinoblastoma susceptibility protein) is expressed can be subjected to this treatment.
Transcriptional Regulatory Network
In recent times, this network has been associated with CDK-cyclin machinery for the regulation of cell cycle. Studies on Saccharomyces cerevisiae showed that most of the genes alter the expression over the course of the cycle and where they maybe transcribed at great levels at one time and remain low during the rest of the cycle. This periodic expression is controlled by transcription factors which are also periodically expressed. These factors are involved in phase-specific gene expression.
While some of these factors identified in cells deficient in S phase and mitotic cyclins continued to be expressed in arrested cells with no cyclin activity, many of them changed their behaviour and stopped expression, which showed they were in some way controlled by the CDK network.
The activation of Cdk/ cyclin complexes require phosphorylation of a conserved Cdk threonine residue at position 160. This is catalyzed by CAK (for Cdk-activating kinase), which is composed of a Cdk (Cdk7) complexed with cyclin H. Complexes of Cdk7 and cyclin H are also associated with the transcription factor TFIIH, which is required for initiation of transcription by RNA polymerase II. This is one such example of how the cyclin-CDK network is interconnected to transcription factors.
Cell Cycle Checkpoints
As discussed briefly, earlier in the introduction, these checkpoints are needed for verifying the state of the cell and repairing it before allowing its progression into the next phase. They comprise a network of regulatory proteins that control cell through the different stages of the cell cycle. It ensures that damaged or incomplete DNA doesn’t get passed on to the daughter cells. The three main checkpoints are: the G1/S checkpoint, the G2/M checkpoint and the metaphase (mitotic) checkpoint.
A regulatory checkpoint called the Restriction point or START is regulated by G1/S cyclins which aid in the transition from G1 phase to S phase. The checkpoint makes sure that the cell has all the requirements to complete replication of DNA in the next phase. If the cell is successful in passing through this check point, it now commits completely to division. The G2/M checkpoint regulated by the p53 tumour suppressor protein ensures the doubled DNA hasn’t sustained any damage. It has the following significance: –
- In case of any damage, the protein either triggers apoptosis (programmed cell death) or repairs the damage.
- If the protein itself is non-functional, as seen in cases of diseases or mutations, the damaged cell will continue to proliferate and become cancerous.
- It ensures that the cell has sufficient cytoplasm and phospholipids to equally distribute into the two daughter cells forming in the future.
- More importantly, it checks whether it is the appropriate time for the cell to enter the mitotic phase and replicate. This proves especially beneficial in case of a growing embryo where symmetric distribution is mandatory.
Breaks in double stranded DNA are usually repaired by two processes in Interphase.
- Non-Homologous End Joining (NHEJ): – It joins broken ends of DNA in all the phases of interphase.
- Homologous Recombinational Repair (HRR): – This process is active during the S and G2 phases only after the partial or complete replication of DNA.
The Metaphase checkpoint makes sure the cell has committed to mitosis once it reaches metaphase. It checks spindle formation, alignment of the chromosomes on the spindle equator prior to anaphase. Completely differentiated cells and non-proliferating cells leave the cycle and remain in the resting state and hence don’t require these checkpoints.
In cancerous cells, the mutation is such that the cells just skip through these checkpoints and move through the phases very quickly. Due to this, any mutation or damage during the interphase will be passed along to the daughter cells. The G0 Checkpoint plays a pivotal role in awakening the oocyte from its pre-fertilisation dormancy, back into the cell cycle after receiving signalling factors released during fertilisation with the sperm. p53 triggers the control mechanisms at both G1/S and G2/M checkpoints along with other factors.
Maturation Promoting Factor
Maturation promoting factor (MPF) causes entry of the oocytes into meiosis and induces entry of somatic cells into M phase of the mitotic cycle. It is composed of two subunits: Cdc2 and cyclin B. Cyclin B is a regulatory subunit required for catalytic activity of the Cdc2 protein kinase. The MPF activity is controlled by the periodic accumulation and degradation of cyclin B during cell cycle progression.
Cyclin B synthesis begins in S phase. Cyclin B then accumulates and forms complexes with Cdc2 throughout S and G2. As these complexes form, Cdc2 is phosphorylated at two regulatory positions. One of these phosphorylations occurs at threonine-161 and is required for Cdc2 kinase activity. The second is a phosphorylation of tyrosine-15, and of the adjacent threonine-14 in vertebrates. Phosphorylation of tyrosine-15 inhibits Cdc2 activity and leads to the accumulation of inactive Cdc2/cyclin B complexes throughout S and G2.
The transition from G2 to M is then brought about by activation of the Cdc2/cyclin B complex as a result of de-phosphorylation of threonine-14 and tyrosine-15 by a protein phosphatase called Cdc25.
- Griffiths, A.J. (2012). Introduction to genetic analysis (10th ed.). New York: W.H.
Freeman and Co. ISBN 9781429229432. OCLC 698085201.
- Golitsin, Y. N.; Krylov, M.C. (2010). Cell division : theory, variants, and degradation. New
York: Nova Science Publishers. p. 137. ISBN 9781611225938. OCLC 669515286.
- Quammen, D. (April 2008). “Contagious Cancer”. Harper’s Magazine. ISSN 0017-789X.
- Retrieved from the World Wide Web:-
- Lindqvist A., Van Z.W., Karlsson R.C, Wolthuis R.M. (May 2007). “Cyclin B1-Cdk1
activation continues after centrosome separation to control mitotic progression”. PLoS
Biology. 5 (5): e123. doi:10.1371/journal.pbio.0050123. PMC 1858714. PMID 17472438
- Lewontin, R.C., Miller, J.H., Gelbart, W.M., Griffiths, A.J. (1999). “The Mechanism of
Crossing-Over”. Modern Genetic Analysis.
- “Researchers Shed Light On Shrinking Of Chromosomes”. ScienceDaily. Retrieved 2019-
- Walter, P., Roberts, K., Raff, M., Lewis, J., Johnson, A., Alberts, B.
(2002). “Mitosis”. Molecular Biology of the Cell (4th ed.).
- Brooker, A.S., Berkowitz, K.M. (2014). “The roles of cohesins in mitosis, meiosis, and
human health and disease”. Methods in Molecular Biology. New York: Springer. 1170:
2_11. ISBN 9781493908875. PMC 4495907. PMID 24906316.
- “The Cell Cycle”. http://www.biology-pages.info. Retrieved 2019-04-14.
- Dekker, J. (2014-11-25). “Two ways to fold the genome during the cell cycle: insights
obtained with chromosome conformation capture”. Epigenetics & Chromatin. 7 (1):25 doi:10.1186/1756-8935-7-25. PMC 4247682. PMID 25435919.
- Gilbert, S.F. (2000). “Oogenesis”. Developmental Biology (6th ed.).
- Guertin, D.A., Trautmann, S., McCollum, D. (2002-06-01). “Cytokinesis in
Eukaryotes”. Microbiology and Molecular Biology Reviews. 66 (2): 155–178 doi:10.1128/MMBR.66.2.155-178.2002. ISSN 1092- PMC 120788. PMID 12040122.
- Spellman, P.T., Sherlock, G., Zhang, M.Q., Iyer, V.R., Anders, K., Eisen, M.B., et al.
(December 1998). “Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization”. Molecular Biology of the
Cell. 9 (12): 3273–97. doi:10.1091/mbc.9.12.3273. PMC 25624. PMID 9843569.
- Robbins, S.L., Cotran, R.S. (2004). Kumar, V., Abbas, A.K., Fausto, N. (eds.). Pathological
Basis of Disease. Elsevier. ISBN 978-81-8147-528-2.
- Dong, P., Maddali, M.V., Srimani, J.K., Thélot, F., Nevins, J.R., Mathey-Prevot, B., You,
L. (September 2014). “Division of labour between Myc and G1 cyclins in cell cycle
commitment and pace control”. Nature Communications. 5: 4750. doi:10.1038/ncomms5750. PMC 4164785.
- Mahmoudi, M., Azadmanesh, K., Shokrgozar, M.A., Journeay, W.S., Laurent, S. (May
2011). “Effect of nanoparticles on the cell life cycle”. Chemical Reviews. 111 (5): 3407– 32 doi:10.1021/cr1003166. PMID 21401073.
- Goel, S., DeCristo, M.J., McAllister, S.S., Zhao, J.J. (November 2018). “CDK4/6
Inhibition in Cancer: Beyond Cell Cycle Arrest”. Trends in Cell Biology. 28 (11): 911– 925 doi:10.1016/j.tcb.2018.07.002. PMC 6689321. PMID 30061045.
- Morgan, D.O. (2007). The cell cycle : principles of control. London: New Science
Press. ISBN 978-0-19-920610-0. OCLC 70173205.
- Paternot, S., Bockstaele, L., Bisteau, X., Kooken, H., Coulonval, K., Roger, P.P. (February 2010). “Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase”. Cell Cycle. 9 (4): 689–99. doi:10.4161/cc.9.4.10611. PMID 20107323.
- Sanidas, I., Morris, R., Fella, K.A., Rumde, P.H., Boukhali, M., Tai, E.C., et al. (March
2019). “A Code of Mono-phosphorylation Modulates the Function of RB”. Molecular
Cell. 73 (5):9851000.e6. doi:10.1016/j.molcel.2019.01.004. PMC 6424368. PMID 30711
- Narasimha, A.M., Kaulich, M., Shapiro, G.S., Choi, Y.J., Sicinski, P., Dowdy, S.F. (June
2014). “Cyclin D activates the Rb tumor suppressor by mono-phosphorylation”. eLife. 3:
e02872. doi:10.7554/eLife.02872. PMC 4076869. PMID 24876129.
- Topacio, B.R., Zatulovskiy, E., Cristea, S., Xie, S., Tambo, C.S., Rubin, S.M., et al. (May
2019). “Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein’s
C-TerminalHelix”. MolecularCell. 74 (4):758– 770.e4. doi:10.1016/j.molcel.2019.03.020. PMC 6800134. PMID 30982746.
- Norbury, C. (1995). “Cdk2 protein kinase (vertebrates)”. In Hardie DG, Hanks S
(eds.). Protein kinase factsBook. Boston: Academic Press. p. 184. ISBN 978-0-12-324719-
- “Presentation on CDC25 PHOSPHATASES: A Potential Target for Novel Anticancer
Agents”. Archived from the original on 3 March 2016. Retrieved 11 March 2010.
- O’Leary, B., Finn, R.S., Turner, N.C. (July 2016). “Treating cancer with selective CDK4/6
inhibitors”. Nature Reviews. Clinical Oncology. 13 (7): 417–30 doi:10.1038/nrclinonc.2016.26. PMID 27030077.
- de Lichtenberg, U., Jensen, L.J., Fausbøll, A., Jensen, T.S., Bork, P., Brunak, S. (April
2005). “Comparison of computational methods for the identification of cell cycle-regulated genes”. Bioinformatics. 21 (7):116471. doi:10.1093/bioinformatics/bti093. PMID 15513999
- Pramila, T., Wu, W., Miles, S., Noble, W.S., Breeden, L.L. (August 2006). “The Forkhead
transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle”. Genes & Development. 20 (16): 2266– 78 doi:10.1101/gad.1450606. PMC 1553209. PMID 16912276.
- Orlando, D.A., Lin, C.Y., Bernard, A., Wang, J.Y., Socolar, J.E., Iversen, E.S., et al. (June
2008). “Global control of cell-cycle transcription by coupled CDK and network
oscillators”. Nature. 453 (7197): 944– 7. doi:10.1038/nature06955. PMC 2736871. PMID 18463633.
- Cooper, G.M., Sunderland, M.A. Sinauer Associates; 2000. The Cell: A Molecular
Approach. 2nd edition.
- LeMaire-Adkins, R., Radke, K., Hunt, P.A. (December 1997). “Lack of checkpoint control
at the metaphase/anaphase transition: a mechanism of meiotic nondisjunction in
mammalian females”. The Journal of Cell Biology. 139 (7): 1611–9. doi:10.1083/jcb.139.7.1611. PMC 2132649. PMID 9412457.
- Shibata, A. Regulation of repair pathway choice at two-ended DNA double-strand breaks. Mutat Res. 2017 Oct;803-805:51-55. doi: 10.1016/j.mrfmmm.2017.07.011. Epub 2017 Jul Review. PMID: 28781144