Difference between revisions of "2013 Group 6 Project"

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'''2010:''' A recent study<ref><pubmed>20200228</pubmed></ref> investigating the origins of the wait-anaphase signal has concluded that there may be more than one mechanism however they are not fully understood. The researchers have proposed that when the Ndc80 nears Aurora B, it produces unbound kinetochores through the reduction of their affinity to bind to microtubules. The other proposed mechanism is via a conformational change in the Mis12 complex which may move the Ndc80 complex closer to KNL-1 within the KMN network such that it catalyzes the assembly of the MCC.
 
'''2010:''' A recent study<ref><pubmed>20200228</pubmed></ref> investigating the origins of the wait-anaphase signal has concluded that there may be more than one mechanism however they are not fully understood. The researchers have proposed that when the Ndc80 nears Aurora B, it produces unbound kinetochores through the reduction of their affinity to bind to microtubules. The other proposed mechanism is via a conformational change in the Mis12 complex which may move the Ndc80 complex closer to KNL-1 within the KMN network such that it catalyzes the assembly of the MCC.
 
<ref><pubmed>20028770</pubmed></ref>
 
  
 
'''2011:''' The Anaphase Catastrophe is a programmed cellular death mechanism (apoptotic) that targets tumour cells that have more than two centrosomes. Tumour cells are able to live with their abnormal number of centrosomes due to a clustering of their centrosomes thanks to special pathways, which allow them to keep the bipolar chromosome segregation seen in normal division. These abnormal cells can then proceed to anaphase with their multipolar spindles and segregate their chromosomes to an unusual number of daughter cells (more than two). All resulting daughter cells will subsequently die; hence this is what is known as anaphase catastrophe. Because it is an intrinsic targeting system for tumour cells, it has been suggested that it may be a target for cancer therapy<ref><pubmed>21288923</pubmed></ref> and warrants further future research.
 
'''2011:''' The Anaphase Catastrophe is a programmed cellular death mechanism (apoptotic) that targets tumour cells that have more than two centrosomes. Tumour cells are able to live with their abnormal number of centrosomes due to a clustering of their centrosomes thanks to special pathways, which allow them to keep the bipolar chromosome segregation seen in normal division. These abnormal cells can then proceed to anaphase with their multipolar spindles and segregate their chromosomes to an unusual number of daughter cells (more than two). All resulting daughter cells will subsequently die; hence this is what is known as anaphase catastrophe. Because it is an intrinsic targeting system for tumour cells, it has been suggested that it may be a target for cancer therapy<ref><pubmed>21288923</pubmed></ref> and warrants further future research.

Revision as of 07:48, 15 May 2013

2013 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7

Anaphase

Introduction

  • Chromosomes split
  • sister chromatids move to poles at opposite ends of cell
  • Around 1% of cell cycle duration?
  • starts with Metaphase to Anaphase transition
  • commences with Anaphase promoting complex which marks inhibitory chaperone Securin - Securin inhibits separase
  • Importance of Anaphase in living replicating organisms[1]

History

Date Description
1871 Alexander Kowalevski was the first to comprehend and then figure out the achromatic spindle.[1]
1879 Walter Flemming discovered the longitudinal splitting of chromosomes when in mitosis.[2]
1925 Edmund Beecher Wilson published a timeless work in a book titled "The Cell in Development and Heredity". This book compares the different stages of the cell mitotic cycle and identifies this division process within different organisms. [3]
1943 Hans Ris Uniquely used live imaging as opposed to photographs and identified two stages in anaphase firstly the shrinking as the chromosomes approach the poles and then the elongating as they move further apart.[4]

Anaphase

Metaphase to Anaphase transition

Metaphase to Anaphase transition

Metaphase-to-anaphase transition is tightly controlled by anaphase-promoting complex (APC) motions. APC promotes the degradation of several proteins that inhibit anaphase.[2] The regulatory protein Cdc20 triggers APC/C at the start of the metaphase-anaphase transition. Cdh1 a membrane protein which is able to control the fate of certain cells, triggers anaphase through the G1 stage of the cell cycle. APC/C specifically targets securin(anaphase inhibitor), Early destruction of this inhibitor is coordinated by nuclear transport factors(Nup98 and Rae1), This mechanism is strictly governed to guarantee appropriate timing of degradation. [3]

Mistakes during this process can cause segregation issues leading to the possible demise of the organism. [5]

Process of sister chromatid separation

PMID: 10403247 - Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1.

PMID: 22580470 - Sororin is a master regulator of sister chromatid cohesion and separation.

PMID: 14681690 - Two mitotic kinesins cooperate to drive sister chromatid separation during anaphase.

PMID: 9335333 - Cohesins: chromosomal proteins that prevent premature separation of sister chromatids.

Anaphase to Telophase

Metaphase to Anaphase transition

Essentially the transition from Anaphase to telophase can take 2 pathways, the conventional or normal pathway involves the co-ordination of Kinetochore and microtubules attachment with the strict dictation from the spindle assembly checkpoint (SAC) where as the other route is basically a "short cut" by passing this checkpoint through a process known as mitotic slippage. The kinetochore is a specific zone located on the chromosomes centromeres. [4] During Anaphase chromatids are pulled apart by the microtubules attached to the kinetochore in the direction of the opposite poles. The organisation of these microtubules is critical for regulation of this phase. [5] Anaphase is defined by the the chromatids separating to become a daughter chromosomes. [6] The SAC is solely responsible for the inhibition of telophase initiation. This checkpoint acts as a government arresting cell processes if there is inadequate supply of kinetochore-microtubule attachments. [7]It should be noted that there are cellular processes that can override and bypass this government through mitotic slippage allowing anaphase lateral entry into telophase. [8]


Kinetochores

Kinetochores

Kinetochore is a proteinaceous structure that gathered at the chromosomal centromere region.[9][10][11] The functions of kinetochores are to facilitate the physical connection between the chromosomes and the spindle microtubules, and also to ensure accurate chromosome separation during anaphase. [12][13][14] During anaphase, kinetochores that are attached to the spindle microtubules are thought to induce a poleward forces to the chromosomes, which causes the chromosomes to move towards the opposite poles. [15][16]

Nonkinetochores

Meiotic cell like oocytes does not contain centrosomes[17][18]. It is found that the kinetochores fibers are not involved in the development of the 1st meiotic spindle or in the meiotic chromosome assembly to the metaphase plate[19]. Instead, the meiotic spindle is gathered around the chromatin through a RanGTP –dependent pathway[20][21]. But, it is discovered that microtubules can self-organize into bipolar spindles if the chromatin in absent (8684481)(17276346) through motor-driven processes[22][23]. The drawback of non-kinetochore cell division is that it displays a random monopolar poleward action, which resembles chromosome nondisjunction during the error-prone meiosis[24][25]. Consequently, this may cause the formation of the aneuploidy cell [26]

Chromosomal motors

Plus-end directed motors

These motors are found at the chromosome arms. They are responsible for the “polar ejection” forces that help in positioning chromosomes at the spindle equator during chromosome congression, and they can also generate forces that help to sustain chromosome movement. [27][28]

Minus-end directed motors

Dynein a minus-end directed motor is mostly found in the kinetochores & the spindle poles [29][30]. Spindle-associated dynein aid in the assembling of spindle.[31][32][33] Kinetochore-associated dynein (KD) is needed to stabilize the connection between kinetochores and microtubules by generating tension on the kinetochore. In addition, KD also plays a role in silencing the spindle-assembly checkpoint (SAC)[34] that function in making sure that the chromosome separation prerequisites have been met and thus decides whether implement or delay the chromosome separation.[35]. Absence or decrease in KD may lead to failure of chromosome congression and reduction in chromosome velocity by ~40% during anaphase, without disturbing the poleward microtubules flux rate. [36]

Spindle fibers

Anaphase in Meiosis

1/ Stages of anaphase in meiosis - then go into depth about proteins and their effect


PMID: 12737807 - Division of the nucleolus and its release of CDC14 during anaphase of meiosis I depends on separase, SPO12, and SLK19.

PMID: 10440376 - Cohesin Rec8 is required for reductional chromosome segregation at meiosis

PMID: 12714746 - Requirement of Cks2 for the first metaphase/anaphase transition of mammalian meiosis

Anaphase in Mitosis

(1) Segregation of sister chromatids (2) Sister chromatids move towards respective poles of the cell, driven by spindle action (3) At the end of anaphase, each pole of the cell will have a complete set of chromosomes.

Molecular aspect of mitosis

Cdk1

Cdk1 is a gene from Ser/Thr protein kinase family. This gene assists in cell cycle regulation. Inactivation of this gene allows the formation of the pre-replicative complexes, which is important for DNA replication [37]. Partial activation of this gene might be required in anaphase during the segregation of the sister chromatids [38].Without the inactivation of Cdk1 gene, chromosomes cannot decondense, nuclear envelopes will not be able to reassemble and cell can’t divide [39][40][41]. This gene is inactivate via cyclin proteolysis mechanism[42].

APC/C

APC/C is activated by binding of cdc20. This protein depends on high Cdk1 activity[43]. In anaphase, APC activity is needed but the APC’s role in cyclin proteolysis is not sufficient to justify its role in commencing anaphase. In order to initiate anaphase, it is crucial for at least one other APC substrate (such as securin) is destroyed[44].

Separase

Separase is a cysteine protein. It is essential in assisting the segregation of sister chromatids. This protein is activated by the proteolysis of securin that is mediated by APC/C. [45]

Cyclin B & Securin

Cyclin b and securin are both the substrate of APC/C. Both the proteins are stable until the initiation of metaphase. Cyclin b and securin degradation will only commence when all chromosomes have attached to the mitotic spindle. This process is mediated by APC/C. The reason is to ensure that the cohesin from sister chromatids are not dissolved before spindle assembly has been completed. Or else this will lead to the missegregation of the sister chromatids, which will cause the formation of aneuploid daughter cell.[46]

Cohesin

Cohesin connects the sister chromatids together. During the transition of metaphase to anaphase, the separase will cleaved the cohesin between the sister chromatids[47][48], which then cause sister chromatids to separate and move towards opposite spindle poles. In higher eukaryotes, like human, there are two different pathways in removing the cohesin[49]. The first pathway occurs during prophase and prometaphase. This pathway depends on Polo-like kinase mechanism[50][51][52]. During this pathway, majority of the cohesin is removed from chromosomes. The second pathway occurs during anaphase due to a small amount of cohesin remains on the chromosomes until the beginning of the anaphase that is normally found in the centromeric region [53][54]. This pathway occurs when separase is activated via APC-dependent securin proteolysis. It removes the remaining cohesin from the chromosome.

Spindle assembly checkpoint

Spindle assembly checkpoint is the biochemical pathway delays the proteolysis of securin & cyclin b until all chromosomes are bipolarly attached to the mitotic spindle [55]. A single unattached kinetochore is enough to delay all sister chromatids segregation [56]. This checkpoint is believed to measure the tension produced at kinetochore when both the sister chromatids are attached to the opposite poles.[57] [58]

Defects resulting from Anaphase malformation

NO REFERENCES AT END OF SENTENCE!!! FIX THIS AND OTHERS IN EDITING!!!

  • If the chromosome tips are damaged during anaphase then cytokinesis cannot occur[59] and therefore the cell cannot divide into two daughter cells, not sure if this is in relation to both mitosis and meiosis but should be interesting to further research. The experimental removal of chromosomal tips shows cell division being delayed, the furrow itself being delayed or even regressing from its ready to divide state.
Cytokinesis defects resulting from chromosomal tip damage during Anaphase
  • APC/C mutants of C. elegans demonstrate defects in germline proliferation, the development of the female vulva and male tail and the metaphase to anaphase transition in meiosis I. Therefore irregularities in the APC[60] contribute to physical deformities in this species. More on Metaphase-to-Anaphase (mat) transition abnormalities leading to defects in C. elegans here: [6]
  • The APC/C has many important roles in the development, function and survival of the nervous system[61]. Incorrect ACP activity leads to some neurological and psychiatric disorders. Research into the APC's role in neurobiology may grant us ways to use the APC to manage neurological disorders such as mental retardation and autism to even neurodegenerative disorders.
  • When the chromosomes do not separate properly in Anaphase, referred to as "nondisjunction"; aneuploidy results[62]. This refers to an abnormal number of chromosomes. A well known one is Trisomy 21 or Down's syndrome in which there are three copies of the 21st chromosome[63]. Others include Patau syndrome, Edward's syndrome, Klinefelter syndrome and Turner's syndrome[64][65][66]
  • Anaphase bridges can cause mutations such as the structural rearrangement of chromosomes which usually lead to the formation of isochromosomes (chromosomes which, after losing one of their arms are replaced with a copy of another arm) and whole-arm translocations, the loss of the entire chromosome through mitotic spindle detachment or faulty cytokinesis in which the failure to divide results in polyploidy (more than 2 copies of a chromosome) and additional centrosomes which may lead to multipolar spindle formations in future mitosis[67]. The presence of chromatin bridges in Anaphase is also linked to chromosomal instability[68] and cancer.

Current research

PMID: 23566798 - this is copyrighted, can we still use copyrighted journals as long as we reference like normal and don't plagiarise anything? Or steal images? [Mark said we can draw our own versions but mention we based them off copyrighted images/ideas for instance]

2008: Correct division of cellular contents between two daughter cells depends upon spatial and temporal cues; anaphases' microtubular system organizes itself at the spindle midzone and functions to orient the cell division plane in the center of the segregating chromosomes. The signalling pathway responsible for this is not understood, but this molecular study[69] explores how the phosphorylation of Aurora B kinase; a regulator of mitosis, ultimately leads to a gradient which centers at the spindle midzone. The study is therefore successful in the discovery of a possible regulatory mechanism for the anaphase phosphorylation gradient, and suggests that its findings may be useful in the future development of a model for anaphases' spatial patterning.

The Anaphase Promoting Complex/Cyclosome or APC/C moderates mitosis by adding ubiquitin chains to cell cycle regulators, to initiate the formation of these chains the APC/C binds ubiquitin to lysine in substrates and elongates chains via lysine residue modification in attached ubiquitin moieties. How the APC/C and ubiquitin ligases are able to change from lysine residues present on substrates to specific ones on ubiquitin is not known, however; recently the method of assembly for the ubiquitin chains that control the APC/C has been determined. It has been found that by the assembly of certain ubiquitin chains the APC/C initiates substrate degradation, a study[70] has hypothesised that via the APC/C's ability to identify patterns in substrates and ubiquitin allows it to build ubiquitin chains that are able to tightly regulate the cell cycle.

2010: A recent study[71] investigating the origins of the wait-anaphase signal has concluded that there may be more than one mechanism however they are not fully understood. The researchers have proposed that when the Ndc80 nears Aurora B, it produces unbound kinetochores through the reduction of their affinity to bind to microtubules. The other proposed mechanism is via a conformational change in the Mis12 complex which may move the Ndc80 complex closer to KNL-1 within the KMN network such that it catalyzes the assembly of the MCC.

2011: The Anaphase Catastrophe is a programmed cellular death mechanism (apoptotic) that targets tumour cells that have more than two centrosomes. Tumour cells are able to live with their abnormal number of centrosomes due to a clustering of their centrosomes thanks to special pathways, which allow them to keep the bipolar chromosome segregation seen in normal division. These abnormal cells can then proceed to anaphase with their multipolar spindles and segregate their chromosomes to an unusual number of daughter cells (more than two). All resulting daughter cells will subsequently die; hence this is what is known as anaphase catastrophe. Because it is an intrinsic targeting system for tumour cells, it has been suggested that it may be a target for cancer therapy[72] and warrants further future research.

  • Figure 2 image from ^ paper is a good image to use for this section, I'm pretty sure it's free but could someone just confirm this with me as I don't want to infringe any copyrights

Suggested research

Contractile forces

It has been known for quite some time that due to the extension of the anaphase spindle, spherical tissue cultured cells will elongate to a capsular shape while preparing for cytokinesis. A study[73] has based itself on further understanding the process of anaphase cell elongation, however it is noted that the functions of equatorial contraction, polar relaxation, and the spindle pushing force remain unknown. Whether cell elongation is a phase in its own right or part of another, and how these cellular processes are controlled are not understood.

APC structure & purpose of mitotic phosphorylation

So far, there have not been any successful vertebrate Anaphase Promoting Complex/Cyclosome (APC/C) reconstitutions from recombinant subunits[74] in vitro and thus the purpose of the multiple mitotic phosphorylations it undergoes as well as what kinases are involved remains a target for study. Current study is therefore limited to APC phosphorylation in vitro in comparison with APC modification in vivo, advances have however been made in the effects of regulation via phosphorylation of CDC20, which is a protein complex associated with the APC which serves to activate it.


- [75]

- [76]

- Research conducted on Saccaromyces cerevisiae has shown that it is damage induced to the DNA, and not the...[77]

Further reading

  • Differences between meiosis and mitosis [7]

Glossary

  • Anaphase Promoting Complex/ Cyclosome (APC/C) - A large protein complex of multiple subunits which activates during cell division and whose purpose it is to signal for anaphase to begin.
  • Cell cycle - The series of events that occur within a cell during its lifetime; divided into phases of growth, replication and division into daughter cells.
  • Chromosome - blah
  • Chromatin bridges - blah
  • Chromatids - blah
  • Chromosome centromere - blah
  • Cytokinesis - The final stage of cell division in both meiosis and mitosis, wherein the cytoplasm of a dividing cell is constricted so that the cell may separate into the products of cellular division, the daughter cells.
  • Kinetochores - blah
  • KMN network: - Along with the more recently discovered Ska complex (consisting of Ska 1-3 subunits) oversee microtubule (MT) attachment to kinetochores (KT), and are thus crucial to proper mitotic division. The KMN is named according to the first letters in KNL1[8], Mis12[9], and Ndc80[10], which are proteins that assist in cell division and constitute the KMN network.
  • Meiosis - One of the two types of cellular division, a reductive type in which the daughter cells, also known as gametes (in males they are sperm cells and in females they are egg cells) are produced. The daughter cells have half the number of chromosomes of the parent cell and are thus termed haploid. Meiosis can be likened to a sort of double mitosis, with the phases being: Interphase, Prophase I, Metaphase I, Anaphase I, Telophase I, Prophase II, Metaphase II, Anaphase II and Telophase II. Four sperm/egg cells are produced which are genetically different to their parent cell with each successful meiotic division, when these cells fuse during sexual reproduction an embryo is created and later develops into a new organism. Oskar Hertwig, a German zoologist, first observed the importance of gametes. [11]
  • Microtubule - blah
  • Mitosis - The other type of cell division, all other cells that are not gametes (somatic cells) undergo mitosis in order to replicate. Cells in the human body replicate in order to reproduce resulting in growth or to repair damaged tissues. Mitosis results in two daughter cells that are genetically identical to the parent cell. No crossing over occurs and the daughter cells are diploid, meaning that they have the exact same number of chromosomes as the parent cell. Daughter cells are therefore essentially clones as the parent cell simply replicates its genetic material and splits into two cells.

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2013 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7

Dr Mark Hill 2013, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G