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The Cell cycle

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1 The Cell cycle on Tue Jul 21, 2015 12:30 pm

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The Cell cycle



The  duplication of eukaryotic cells is a all fine-tuned biochemical processes that depend on the precise structural arrangement of the cellular components. 2

The only way to make a new cell is to duplicate a cell that already exists.

That raises  the question how the first cell could have emerged  

This simple fact, first established in the middle of the nineteenth century, carries with it a profound message for the continuity of life. All living organisms, from the unicellular bacterium to the multicellular mammal, are products of repeated rounds of cell growth and division extending back in time to the beginnings of life. A cell reproduces by performing an orderly sequence of events in which it duplicates its contents and then divides in two.

Question : how was the right orderly sequence of events achieved ? Is not forsight and order right from the beginning required ?

 
This cycle of duplication and division, known as the cell cycle, is the essential mechanism by which all living things reproduce. In unicellular species, such as bacteria and yeasts, each cell division produces a complete new organism. In multicellular species, long and complex sequences of cell divisions are required to produce a functioning organism. Even in the adult body, cell division is usually needed to replace cells that die. In fact, each of us must manufacture many millions of cells every second simply to survive: if all cell division were stopped—by exposure to a very large dose of x-rays, for example—we would die within a few days. The details of the cell cycle vary from organism to organism and at different times in an organism’s life. Certain characteristics, however, are universal. At a minimum, the cell must accomplish its most fundamental task: the passing on of its genetic information to the next generation of cells. To produce two genetically identical daughter cells, the DNA in each chromosome must first be faithfully replicated to produce two complete copies. The replicated chromosomes must then be accurately distributed (segregated) to the two daughter cells, so that each receives a copy of the entire genome.

The Mitotic Cell Cycle




Metaphase, Anaphase and Telophase

Part one of this series looked at the cycles within cycles that make up the existence of a cell. Whilst taking up such a small percentage of the overall cell cycle, mitosis is one of the most important series of events in the life of a cell.  1

Mitosis divides the nucleus of a cell into two new nuclei.
The first stage of mitosis is prophase. Here we see the DNA has wrapped tightly around
proteins to form chromosomes, the nucleolus disappears, and microtubules begin to grow
out from the centrosomes.
The next stage is prometaphase where the nuclear membrane breaks down.
In prometaphase, the microtubules also lengthen by the addition of tubulin proteins to the growing end.
The microtubules then attach to the chromosomes at the kinetochore--a protein complex located at the
centromere of each chromosome.
In prometaphase, the microtubules also lengthen by the addition of tubulin proteins to the
growing end. The microtubules then attach to the chromosomes at the kinetochore--a protein
complex located at the centromere of each chromosome.
In metaphase, the chromosomes align at the equator of the cell.
In anaphase, the sister chromatids are separated. The separation occurs when the microtubules
 connected to the chromatids shorten by the loss of tubulin.

Also, the microtubules not connected to the chromatids lengthen to push the two poles of the cell apart.
In telophase, the spindle apparatus made up of microtubules breaks down.
After the spindle apparatus breaks down, the nuclear membrane reforms, and the chromosome uncoil.
Finally, at the end of telophase, the nucleolus reappears. Mitosis is now complete.

In addition to duplicating their genome, most cells also duplicate their other organelles and macromolecules; otherwise, daughter cells would get smaller with each division. To maintain their size, dividing cells must coordinate their growth (that is, their increase in cell mass) with their division.  We begin with a brief overview of the cell cycle. We then describe the cell-cycle control system, a complex network of regulatory proteins that triggers the different events of the cycle. We next consider in detail the major stages of the cell cycle, in which the chromosomes are duplicated and then segregated into the two daughter cells. Finally, we consider how extracellular signals govern the rates of cell growth and division and how these two processes are coordinated.
OVERVIEW OF THE CELL CYCLE


The most basic function of the cell cycle is to duplicate the vast amount of DNA in the chromosomes and then segregate the copies into two genetically identical daughter cells. These processes define the two major phases of the cell cycle. Chromosome duplication occurs during S phase (S for DNA synthesis), which requires 10–12 hours and occupies about half of the cell-cycle time in a typical mammalian cell. After S phase, chromosome segregation and cell division occur in M phase (M for mitosis), which requires much less time (less than an hour in a mammalian cell). M phase comprises two major events: nuclear division, or mitosis, during which the copied chromosomes are distributed into a pair of daughter nuclei; and cytoplasmic division, or cytokinesis, when the cell itself divides in two 

At the end of S phase, the DNA molecules in each pair of duplicated chromosomes are intertwined and held tightly together by specialized protein linkages. Early in mitosis at a stage called prophase, the two DNA molecules are gradually disentangled and condensed into pairs of rigid, compact rods called sister chromatids, which remain linked by sister-chromatid cohesion. When the nuclear envelope disassembles later in mitosis, the sister-chromatid pairs become attached to the mitotic spindle, a giant bipolar array of microtubules . Sister chromatids are attached to opposite poles of the spindle and, eventually, align at the spindle equator in a stage called metaphase. The destruction of sister-chromatid cohesion at the start of anaphase separates the sister chromatids, which are pulled to opposite poles of the spindle. The spindle is then disassembled, and the segregated chromosomes are packaged into separate nuclei at telophase. Cytokinesis then cleaves the cell in two, so that each daughter cell inherits one of the two nuclei.





The Eukaryotic Cell Cycle Usually Consists of Four Phases


Most cells require much more time to grow and double their mass of proteins and organelles than they require to duplicate their chromosomes and divide. Partly to allow time for growth, most cell cycles have gap phases—a G1 phase between M phase and S phase and a G2 phase between S phase and mitosis. Thus, the eukaryotic cell cycle is traditionally divided into four sequential phases: G1, S, G2, and M. G1, S, and G2 together are called interphase . In a typical human cell proliferating in culture, interphase might occupy 23 hours of a 24-hour cycle, with 1 hour for M phase. Cell growth occurs throughout the cell cycle, except during mitosis. The two gap phases are more than simple time delays to allow cell growth. They also provide time for the cell to monitor the internal and external environment. to ensure that conditions are suitable and preparations are complete before the cell commits itself to the major upheavals of S phase and mitosis. The G1 phase is especially important in this respect. Its length can vary greatly depending on external conditions and extracellular signals from other cells. If extracellular conditions are unfavorable, for example, cells delay progress through G1 and may even enter a specialized resting state known as G0 (G zero), in which they can remain for days, weeks, or even years before resuming proliferation. Indeed, many cells remain permanently in G0 until they or the organism dies. If extracellular conditions are favorable and signals to grow and divide are present, cells in early G1 or G0 progress through a commitment point near the end of G1 known as Start (in yeasts) or the restriction point (in mammalian cells). We will use the term Start for both yeast and animal cells. After passing this point, cells are committed to DNA replication, even if the extracellular signals that stimulate cell growth and division are removed.

Cell-Cycle Control Is Similar in All Eukaryotes


Some features of the cell cycle, including the time required to complete certain events, vary greatly from one cell type to another, even in the same organism. The basic organization of the cycle, however, is essentially the same in all eukaryotic cells, and all eukaryotes appear to use similar machinery and control mechanisms to drive and regulate cell-cycle events. The proteins of the cell-cycle control system  have been so well conserved  that many of them function perfectly when transferred from a human cell to a yeast cell. We can therefore study the cell cycle and its regulation in a variety of organisms and use the findings from all of them to assemble a unified picture of how eukaryotic cells divide. Several model organisms are used in the analysis of the eukaryotic cell cycle. The budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe are simple eukaryotes in which powerful molecular and genetic approaches can be used to identify and characterize the genes and proteins that govern the fundamental features of cell division. The early embryos of certain animals, particularly those of the frog Xenopus laevis, are excellent tools for biochemical dissection of cell-cycle control mechanisms, while the fruit fly Drosophila melanogaster is useful for the genetic analysis of mechanisms underlying the control and coordination of cell growth and division in multicellular organisms. Cultured human cells provide an excellent system for the molecular and microscopic exploration of the complex processes by which our own cells divide.

Summary


Cell division usually begins with duplication of the cell’s contents, followed by distribution of those contents into two daughter cells. Chromosome duplication occurs during S phase of the cell cycle, whereas most other cell components are duplicated continuously throughout the cycle. During M phase, the replicated chromosomes are segregated into individual nuclei (mitosis), and the cell then splits in two (cytokinesis). S phase and M phase are usually separated by gap phases called G1 and G2, when various intracellular and extracellular signals regulate cell-cycle progression. Cell-cycle organization and control have been highly conserved during evolution, and studies in a wide range of systems have led to a unified view of eukaryotic cell-cycle control



1) http://tfscientist.hubpages.com/hub/Stages-of-the-Cell-Cycle-Mitosis-Part-2-of-2
2) http://foresight.org/Conference/MNT6/Abstracts/Knoch/index.html



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2 THE CELL-CYCLE CONTROL SYSTEM on Tue Jul 21, 2015 5:58 pm

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THE CELL-CYCLE CONTROL SYSTEM





For many years, cell biologists watched the puppet show of DNA synthesis, mitosis, and cytokinesis but had no idea of what lay behind the curtain controlling these events. It was not even clear whether there was a separate control system, or whether the processes of DNA synthesis, mitosis, and cytokinesis somehow controlled themselves. A major breakthrough came in the late 1980s with the identification of the key proteins of the control system, along with the realization that they are distinct from the proteins that perform the processes of DNA replication, chromosome segregation, and so on. In this section, we first consider the basic principles upon which the cell-cycle control system operates. We then discuss the protein components of the system and how they work together to time and coordinate the events of the cell cycle.

The Cell-Cycle Control System Triggers the Major Events of the Cell Cycle



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The cell-cycle control system operates much like a timer that triggers the events of the cell cycle in a set sequence



In its simplest form the control system is rigidly programmed to provide a fixed amount of time for the completion of each cell-cycle event.  The control system in these early embryonic divisions is independent of the events it controls, so that its timing mechanisms continue to operate even if those events fail. In most cells, however, the control system does respond to information received back from the processes it controls If some malfunction prevents the successful completion of DNA synthesis, for example, signals are sent to the control system to delay progression to M phase. Such delays provide time for the machinery to be repaired and also prevent the disaster that might result if the cycle progressed prematurely to the next stage—and segregated incompletely replicated chromosomes, for example. The cell-cycle control system is based on a connected series of biochemical switches, each of which initiates a specific cell-cycle event. This system of switches possesses many important features that increase the accuracy and reliability of cell-cycle progression. First, the switches are generally binary (on/off) and launch events in a complete, irreversible fashion. It would clearly be disastrous, for example, if events like chromosome condensation or nuclear-envelope breakdown were only partially initiated or started but not completed. Second, the cell-cycle control system is remarkably robust and reliable, partly because backup mechanisms and other features allow the system to operate effectively under a variety of conditions and even if some components fail. Finally, the control system is highly adaptable and can be modified to suit specific cell types or to respond to specific intracellular or extracellular signals.

The Cell-Cycle Control System Depends on Cyclically Activated Cyclin-Dependent Protein Kinases (Cdks)

Central components of the cell-cycle control system are members of a family of protein kinases known as  Cyclin-dependent kinases (Cdks). The activities of these kinases rise and fall as the cell progresses through the cycle, leading to cyclical changes in the phosphorylation of intracellular proteins that initiate or regulate the major events of the cell cycle. An increase in Cdk activity at the G2/M transition, for example, increases the Phosphorylation of proteins that control chromosome condensation, nuclear-envelope breakdown, spindle assembly, and other events that occur in early mitosis. Cyclical changes in Cdk activity are controlled by a complex array of enzymes and other proteins. The most important of these Cdk regulators are proteins known as cyclins. Cdks, as their name implies, are dependent on cyclins for their activity: unless they are bound tightly to a cyclin, they have no protein kinase activity.



CDK1 is the only essential cell cycle CDK in human cells and is required for successful completion of M-phase. It is the founding member of the CDK family and is conserved across all eukaryotes. 1



Cyclins were originally named because they undergo a cycle of synthesis and degradation in each cell cycle. The levels of the Cdk proteins, by contrast, are constant. Cyclical changes in cyclin protein levels result in the cyclic assembly and activation of cyclin–Cdk complexes at specific stages of the cell cycle.

Cyclins 2 are generally very different from each other in primary structure, or amino acid sequence. However, all members of the cyclin family are similar in 100 amino acids that make up the cyclin box. Cyclins contain two domains of similar all-α fold, the first located at the N-terminus and the second at the C-terminus. All cyclins are believed to contain a similar tertiary structure of two compact domains of 5 α helices. The first of which is the conserved cyclin box, outside of which cyclins are divergent. For example, the amino-terminal regions of S and M cyclins contain short destruction-box motifs that target these proteins for proteolysis in mitosis.



Cyclins were originally named because they undergo a cycle of synthesis and degradation in each cell cycle. The levels of the Cdk proteins, by contrast, are constant. Cyclical changes in cyclin protein levels result in the cyclic assembly and activation of cyclin–Cdk complexes at specific stages of the cell cycle. There are four classes of cyclins, each defined by the stage of the cell cycle at which they bind Cdks and function. All eukaryotic cells require three of these classes



1. G1/S-cyclins activate Cdks in late G1 and thereby help trigger progression through Start, resulting in a commitment to cell-cycle entry. Their levels fall in S phase.

2. S-cyclins bind Cdks soon after progression through Start and help stimulate chromosome duplication. S-cyclin levels remain elevated until mitosis, and these cyclins also contribute to the control of some early mitotic events.

3. M-cyclins activate Cdks that stimulate entry into mitosis at the G2/M transition. M-cyclin levels fall in mid-mitosis. In most cells, a fourth class of cyclins, the G1-cyclins, helps govern the activities of the G1/S-cyclins, which control progression through Start in late G1. In yeast cells, a single Cdk protein binds all classes of cyclins and triggers different cell-cycle events by changing cyclin partners at different stages of the cycle. In vertebrate cells, by contrast, there are four Cdks. Two interact with G1-cyclins, one with G1/S- and S-cyclins, and one with S- and M-cyclins. In this chapter, we simply refer to the different cyclin–Cdk complexes as G1-Cdk, G1/S-Cdk, S-Cdk, and M-Cdk.

How do different cyclin–Cdk complexes trigger different cell-cycle events? The answer, at least in part, seems to be that the cyclin protein does not simply activate its Cdk partner but also directs it to specific target proteins. As a result, each cyclin–Cdk complex phosphorylates a different set of substrate proteins. The same cyclin–Cdk complex can also induce different effects at different times in the cycle, probably because the accessibility of some Cdk substrates changes during the cell cycle. Certain proteins that function in mitosis, for example, may become available for phosphorylation only in G2.

Studies of the three-dimensional structures of Cdk and cyclin proteins have revealed that, in the absence of cyclin, the active site in the Cdk protein is partly obscured by a protein loop, like a stone blocking the entrance to a cave (Figure A). Cyclin binding causes the loop to move away from the active site, resulting in partial activation of the Cdk enzyme (Figure B). Full activation of the cyclin–Cdk complex then occurs when a separate kinase, the Cdk-activating kinase (CAK), phosphorylates an amino acid near the entrance of the Cdk active site. This causes a small conformational change that further increases the activity of the Cdk, allowing the kinase to phosphorylate its target proteins effectively and thereby induce specific cell-cycle events (Figure C).



Cdk Activity Can Be Suppressed By Inhibitory Phosphorylation and Cdk Inhibitor Proteins (CKIs)

The rise and fall of cyclin levels is the primary determinant of Cdk activity during the cell cycle. Several additional mechanisms, however, help control Cdk activity
at specific stages of the cycle. Phosphorylation at a pair of amino acids in the roof of the kinase active site inhibits the activity of a cyclin–Cdk complex. Phosphorylation of these sites by a protein kinase known as Wee1 inhibits Cdk activity, while dephosphorylation of these sites by a phosphatase known as Cdc25 increases Cdk activity



We will see later that this regulatory mechanism is particularly important in the control of M-Cdk activity at the onset of mitosis. Binding of Cdk inhibitor proteins (CKIs) inactivates cyclin–Cdk complexes. The three-dimensional structure of a cyclin–Cdk–CKI complex reveals that CKI binding stimulates a large rearrangement in the structure of the Cdk active site, rendering it inactive



Cells use CKIs primarily to help govern the activities of G1/S- and S-Cdks early in the cell cycle.

Regulated  proteolysis Triggers the  Metaphase to Anaphase transition


Whereas activation of specific cyclin–Cdk complexes drives progression through the Start and G2/M transitions, progression through the metaphase-to-anaphase transition is triggered not by protein phosphorylation but by protein destruction, leading to the final stages of cell division. The key regulator of the metaphase-to-anaphase transition is the anaphasepromoting complex, or cyclosome (APC/C) , a member of the ubiquitin ligase family of enzymes.



These enzymes are used in numerous cell processes to stimulate the proteolytic destruction of specific regulatory proteins. They  polyubiquitylate specific target proteins, resulting in their destruction in proteasomes. Other ubiquitin ligases mark proteins for purposes other than destruction. The APC/C catalyzes the ubiquitylation and destruction of two major types of proteins. The first is securin, which protects the protein linkages that hold sister-chromatid pairs together in early mitosis. Destruction of securin in metaphase activates a protease that separates the sisters and unleashes anaphase, as described later. The S- and M-cyclins are the second major targets of the APC/C. Destroying these cyclins inactivates most Cdks in the cell. As a result, the many proteins phosphorylated by Cdks from S phase to early mitosis are dephosphorylated by various phosphatases in the anaphase cell. This dephosphorylation of Cdk targets is required for the completion of M phase, including the final steps in mitosis and then cytokinesis. Following its activation in mid-mitosis, the APC/C remains active in G1 to provide a stable period of Cdk inactivity. When G1/S-Cdk is activated in late G1, the APC/C is turned off, thereby allowing cyclin accumulation in the next cell cycle.

The cell-cycle control system also uses another ubiquitin ligase called SCF.



It has many functions in the cell, but its major role in the cell cycle is to ubiquitylate certain CKI proteins in late G1, thereby helping to control the activation of S-Cdks and DNA replication. SCF is also responsible for the destruction of G1/S-cyclins in early S phase. The APC/C and SCF are both large, multisubunit complexes with some related components
, but they are regulated differently. APC/C activity changes during the cell cycle, primarily as a result of changes in its association with an activating subunit—either Cdc20 in mid-mitosis or Cdh1 from late mitosis through early G1. These subunits help the APC/C recognize its target proteins



(Figure A above). SCF activity depends on substrate-binding subunits called F-box proteins. Unlike APC/C activity, however, SCF activity is constant during the cell
cycle. Ubiquitylation by SCF is controlled instead by changes in the phosphorylation state of its target proteins, as F-box subunits recognize only specifically
phosphorylated proteins (Figure B).

Cell-Cycle Control Also Depends on Transcriptional Regulation

In the simple cell cycles of early animal embryos, gene transcription does not occur. Cell-cycle control depends exclusively on post-transcriptional mechanisms that involve the regulation of Cdks and ubiquitin ligases and their target proteins. In the more complex cell cycles of most cell types, however, transcriptional control provides an important additional level of regulation. Changes in cyclin gene transcription, for example, help control cyclin levels in most cells. A variety of methods  have been used to analyze changes in the expression of all genes in the genome as the cell progresses through the cell cycle. The results of these studies are surprising. In budding yeast, for example, about 10% of the genes encode mRNAs whose levels oscillate during the cell cycle. Some of these genes encode proteins with known cell-cycle functions, but the functions of many others are unknown.

1) http://www.nature.com/ncomms/2015/150413/ncomms7769/abs/ncomms7769.html
2) https://en.wikipedia.org/wiki/Cyclin



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The Cell-Cycle Control System Functions as a Network of Biochemical Switches

The major chromosomal events of the cell cycle occur in S phase, when the chromosomes are duplicated, and M phase, when the duplicated chromosomes are segregated
into a pair of daughter nuclei (in mitosis), after which the cell itself divides into two (cytokinesis).

The proteins of the cell-cycle control system  are functionally linked to form a robust network, which operates essentially autonomously to activate a series of biochemical switches, each of which triggers a specific cell-cycle event.

When conditions for cell proliferation are right, various external and internal signals stimulate the activation of G1-Cdk, which in turn stimulates the expression of genes encoding G1/S- and S-cyclins



The resulting activation of G1/S-Cdk then drives progression through the Start transition. G1/S-Cdks unleash a wave of S-Cdk activity, which initiates chromosome duplication in S phase and also contributes to some early events of mitosis. M-Cdk activation then triggers progression through the G2/M transition and the events of early mitosis, leading to the alignment of sister-chromatid pairs at the equator of the mitotic spindle. Finally, the APC/C, together with its activator Cdc20, triggers the destruction of securin and cyclins, thereby unleashing sister-chromatid separation and segregation and the completion of mitosis. When mitosis is complete, multiple mechanisms collaborate to suppress Cdk activity, resulting in a stable G1 period. We are now ready to discuss these cell-cycle stages in more detail, starting with S phase.


Summary

The cell-cycle control system triggers the events of the cell cycle and ensures that they are properly timed and coordinated with each other. The control system responds to various intracellular and extracellular signals and arrests the cycle when the cell either fails to complete an essential cell-cycle process or encounters unfavorable environmental or intracellular conditions. Central components of the control system are the cyclin-dependent protein kinases (Cdks), which depend on cyclin subunits for their activity. Oscillations in the activities of different cyclin–Cdk complexes control various cell-cycle events. Thus, activation of S-phase cyclin–Cdk complexes (S-Cdk) initiates S phase, whereas activation
of M-phase cyclin–Cdk complexes (M-Cdk) triggers mitosis. The mechanisms that control the activities of cyclin–Cdk complexes include phosphorylation of the Cdk subunit, binding of Cdk inhibitor proteins (CKIs), proteolysis of cyclins, and changes in the transcription of genes encoding Cdk regulators. The cell-cycle control system also depends crucially on two additional enzyme complexes, the APC/C and SCF ubiquitin ligases, which catalyze the ubiquitylation and consequent destruction of specific regulatory proteins that control critical events in the cycle.


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4 Re: The Cell cycle on Thu Jul 23, 2015 6:20 am

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S PHASE

Duplication of the chromosomes in S phase involves the accurate replication of the entire DNA molecule in each chromosome, as well as the duplication of the chromatin proteins that associate with the DNA and govern various aspects of chromosome function. Chromosome duplication is triggered by the activation of S-Cdk, which activates proteins that unwind the DNA and initiate its replication at replication origins. Once a replication origin is activated, S-Cdk also inhibits proteins that are required to allow that origin to initiate DNA replication again. Thus, each origin is fired once and only once in each S phase and cannot be reused until the next cell cycle.


The linear chromosomes of eukaryotic cells are vast and dynamic assemblies of DNA and protein, and their duplication is a complex process that takes up a major fraction of the cell cycle. Not only must the long DNA molecule of each chromosome be duplicated accurately—a remarkable feat in itself—but the protein packaging surrounding each region of that DNA must also be reproduced, ensuring that the daughter cells inherit all features of chromosome structure. The central event of chromosome duplication—DNA replication—poses two problems for the cell. First, replication must occur with extreme accuracy to minimize the risk of mutations in the next cell generation. Second, every nucleotide in the genome must be copied once, and only once, to prevent the damaging effects of gene amplification.  Sophisticated protein machinery  performs DNA replication with astonishing speed and accuracy. In this section, we consider the elegant mechanisms by which the cell-cycle control system initiates the replication process and, at the same time, prevents it from happening more than once per cycle.[/b]

S-Cdk Initiates DNA Replication Once Per Cycle

DNA replication begins at origins of replication, which are scattered at numerous locations in every chromosome. During S phase, DNA replication is initiated at these origins when a DNA helicase unwinds the double helix and DNA replication enzymes are loaded onto the two single-stranded templates. This leads to the elongation phase of replication, when the replication machinery moves outward from the origin at two replication forks.

To ensure that chromosome duplication occurs only once per cell cycle, the initiation phase of DNA replication is divided into two distinct steps that occur at
different times in the cell cycle



The first step occurs in late mitosis and early G1, when a pair of inactive DNA helicases is loaded onto the replication origin, forming a large complex called the prereplicative complex or preRC. This step is sometimes called licensing of replication origins because initiation of DNA synthesis is permitted only at origins containing a preRC. The second step occurs in S phase, when the DNA helicases are activated, resulting in DNA unwinding and the initiation of DNA synthesis. Once a replication origin has been fired in this way, the two helicases move out from the origin with the replication forks, and that origin cannot be reused until a new preRC is assembled there at the end of mitosis. As a result, origins can be activated only once per cell cycle.



Above figure illustrates some of the molecular details underlying the control of the two steps in the initiation of DNA replication. A key player is a large multiprotein complex called the origin recognition complex (ORC), which binds to replication origins throughout the cell cycle. In late mitosis and early G1, the proteins Cdc6 and Cdt1 collaborate with the ORC to load the inactive DNA helicases around the DNA next to the origin. The resulting large complex is the preRC, and the origin is now licensed for replication. At the onset of S phase, S-Cdk triggers origin activation by phosphorylating specific initiator proteins, which then nucleate the assembly of a large protein complex that activates the DNA helicase and recruits the DNA synthesis machinery. Another protein kinase called DDK is also activated in S phase and helps drive origin activation by phosphorylating specific subunits of the DNA helicase. At the same time as S-Cdk initiates DNA replication, several mechanisms prevent assembly of new preRCs. S-Cdk phosphorylates and thereby inhibits the ORC and Cdc6 proteins. Inactivation of the APC/C in late G1 also helps turn off preRC assembly. In late mitosis and early G1, the APC/C triggers the destruction of a Cdt1 inhibitor called geminin, thereby allowing Cdt1 to be active. When the APC/C is turned off in late G1, geminin accumulates and inhibits the Cdt1 that is not associated with DNA. Also, the association of Cdt1 with a protein at active replication forks stimulates Cdt1 destruction. In these various ways, preRC formation is prevented from S phase to mitosis, thereby ensuring that each origin is fired only once per cell cycle. How, then, is the cell-cycle control system reset to allow replication in the next cell cycle? At the end of mitosis, APC/C activation leads to the inactivation of Cdks and the destruction of geminin. ORC and Cdc6 are dephosphorylated and Cdt1 is activated, allowing preRC assembly to prepare the cell for the next S phase.

Chromosome Duplication Requires Duplication of Chromatin Structure

The DNA of the chromosomes is extensively packaged in a variety of protein components, including histones and various regulatory proteins involved in the control of gene expression. Thus, duplication of a chromosome is not simply a matter of replicating the DNA at its core but also requires the duplication of these chromatin proteins and their proper assembly on the DNA. The production of chromatin proteins increases during S phase to provide the raw materials needed to package the newly synthesized DNA. Most importantly, S-Cdks stimulate a large increase in the synthesis of the four histone subunits that form the histone octamers at the core of each nucleosome. These subunits are
assembled into nucleosomes on the DNA by nucleosome assembly factors, which typically associate with the replication fork and distribute nucleosomes on both strands of the DNA as they emerge from the DNA synthesis machinery. Chromatin packaging helps to control gene expression. In some parts of the chromosome, the chromatin is highly condensed and is called heterochromatin, whereas in other regions it has a more open structure and is called euchromatin. These differences in chromatin structure depend on a variety of mechanisms, including modification of histone tails and the presence of non-histone proteins. Because these differences are important in gene regulation,it is crucial that chromatin structure, like the DNA within, is reproduced accurately during S phase. How chromatin structure is reproduced is not well understood, however. During DNA synthesis, histone-modifying enzymes and various non-histone proteins are probably deposited onto the two new DNA strands as they emerge from the replication fork, and these proteins are thought to reproduce the local chromatin structure of the parent chromosome. 

Cohesins Hold Sister Chromatids Together

At the end of S phase, each replicated chromosome consists of a pair of identical sister chromatids glued together along their length. This sister-chromatid cohesion sets the stage for a successful mitosis because it greatly facilitates the attachment of the two sister chromatids to opposite poles of the mitotic spindle. Imagine how difficult it would be to achieve this bipolar attachment if sister chromatids were allowed to drift apart after S phase. Indeed, defects in sister-chromatid cohesion— in yeast mutants, for example—lead inevitably to major errors in chromosome segregation. Sister-chromatid cohesion depends on a large protein complex called cohesin, which is deposited at many locations along the length of each sister chromatid as the DNA is replicated in S phase. Two of the subunits of cohesin are members of a large family of proteins called SMC proteins (for Structural Maintenance of Chromosomes). Cohesin forms giant ringlike structures, and it has been proposed that these surround the two sister chromatids



Sister-chromatid cohesion also results, at least in part, from DNA catenation, the intertwining of sister DNA molecules that occurs when two replication forks meet during DNA synthesis.

The enzyme topoisomerase II gradually disentangles the catenated sister DNAs between
S phase and early mitosis by cutting one DNA molecule, passing the other through the break,
and then resealing the cut DNA



Picture below: The DNA-helix-passing reaction catalyzed by DNA topoisomerase II. Unlike type I topoisomerases, type II enzymes hydrolyze ATP (red), which is needed to release and reset the enzyme after each cycle. Type II topoisomerases are largely confined to proliferating cells in eukaryotes; partly for that reason, they have been effective targets for anticancer drugs. Some of these drugs inhibit topoisomerase II at the third step in the figure and thereby produce high levels of double-strand breaks that kill rapidly
dividing cells. The small yellow circles represent the phosphates in the DNA backbone that become covalently bonded to the topoisomerase



Topoisomerase II forms a covalent linkage to both strands of the DNA helix at the same time, making a transient double-strand break in the helix. These enzymes are activated by sites on chromosomes where two double helices cross over each other such as those generated by supercoiling in front of a replication fork

Once a topoisomerase II molecule binds to such a crossing site, the protein uses ATP hydrolysis to perform the following set of reactions efficiently:

(1) it breaks one double helix reversibly to create a DNA “gate”;
(2) it causes the second, nearby double helix to pass through this opening; and
(3) it then reseals the break and dissociates from the DNA. At crossover points generated by supercoiling, passage of the double helix through the gate occurs in the direction that will reduce supercoiling. In this way, type II topoisomerases can relieve the overwinding tension generated in front of a replication fork. Their reaction mechanism also allows type II DNA topoisomerases to efficiently separate two interlocked DNA circles. Topoisomerase II also prevents the severe DNA tangling problems that would otherwise arise during DNA replication. This role is nicely illustrated by mutant yeast cells that produce, in place of the normal topoisomerase II, a version that is inactive above 37°C. When the mutant cells are warmed to this temperature, their daughter chromosomes remain intertwined after DNA replication and are unable to separate. The enormous usefulness of topoisomerase II for untangling chromosomes can readily be appreciated by anyone who has struggled to remove a tangle from a fishing line without the aid of scissors.

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5 Re: The Cell cycle on Wed Dec 21, 2016 3:49 am

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New Research May Change Accepted View of Cell Cycle Control 1

The cells of organisms move through growth stages, duplicating DNA and eventually dividing, and control of that cycle was thought to be understood. The 2001 Nobel Prize in Physiology or Medicine was awarded for the demonstration that the cyclin-dependent kinase complex regulates the cell cycle. New work however, has followed up on some of the unexplained questions remaining in cell cycle control; researchers have discovered that a metabolic oscillator acts as the conductor of cell division.

Some data has stood at odds with the accepted view; cells can divide in the absence of the cyclin machinery, for one. For another, in cells where the cycle is arrested, proteins of the late cell-cycle keep on oscillating. "But there were signs that [we didn't have] the complete story," said University of Groningen system biologist Matthias Heinemann. "We knew that metabolism often oscillated in synchrony with the cell cycle. So maybe, this was an autonomous control mechanism."

Heinemann looked at yeast cells growing in microfluidic channels so individual cells could be observed under a microscope for several days. The addition of fluorescent markers enabled the measurement of metabolic markers NADH, an electron carrier, and ATP, an energy source. From that, changes in the levels of those molecules that indicated clear oscillations were seen, usually moving along with the cell cycle. Heinemann added, "But we also noticed that occasionally cells did not divide, and that these cells still showed metabolic oscillations."

Metabolism appeared to be oscillating independently of the cell cycle; well fed cells had rapid oscillations, poorly fed cells oscillated slowly. "We argue that metabolism and the cyclin-dependent kinase complex are coupled oscillators, which together orchestrate the growth and division of eukaryotic cells, but when metabolism is slowed down or sped up too much, the cell cycle can't keep up and stops," said Heinemann. The cyclin-dependent kinase complex moves to the rhythm of the metabolic oscillations, until it can't keep up. The graphical abstract from their work, published in Molecular Cell, is shown above.

The researchers suggest a system where the metabolic oscillations push the cyclin-dependent kinase complex through the cycle, controlling the timing of the various cell cycle stages. This new work could change a lot of textbooks.

"The current view is too narrow and cannot explain why cells still divide when part of the cyclin-dependent kinase complex is removed," commented Heinemann. It is logical that evolution would favor a focus on the workings of metabolism. "You would expect the earliest cells or proto-cells to have a simple control system to regulate division, and metabolism would be the obvious candidate." This new work could influence clinical research as well. "Most tumor cells have a very high metabolism. Interfering with metabolic processes could be a way to stop them from proliferating."

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