Information

Eukaryotic Life Cycles - Biology

Eukaryotic Life Cycles - Biology


We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

1. Description of Eukaryotic Life Cycles

In Biology, a life cycle (or life history) describes the course of development of an organism. A life cycle is the entire history of an organism, usually shown through a series of developmental stages that depicts the changes a species goes through as they pass from the start of a given developmental stage to the inception of the same developmental stage in the next generation.

The key differences between eukaryotic life cycles is the amount of time spent in haploid vs. diploid phases and the meiotic products (spores vs. gametes) that are produced. Recall that haploid cells contain only one set of chromosomes (n). Diploid cells contain two sets of chromosomes (2n). Meiosis is the process by which diploid cells divide twice in a row after replicating their chromosomes only once. The result is that each final daughter cell is haploid and contains only one copy of each chromosome. This differs from mitosis, when cells divide but the number of chromosome sets stays the same. In mitosis, haploid cells divide to form haploid cells and diploid cells divide to form diploid cells.

Diploid cells contain 2 copies of their genome, they typically:

1. Provide genetic redundancy which can increase resistance to DNA damage (there is a "back-up" copy of DNA in the event that one gets damaged).
2. Benefit from genetic exchange with other individuals, which can potentially provide more genetic diversity and thus offers a greater potential for survival in a changing environment.
3. Have slower growth because they have a longer cell cycle due to a greater amount of DNA to be replicated with each cell division.

Since haploid cells have only one copy of their genome they are typically:

1. More vulnerable to genetic damage (no "back-up" copy of DNA).
2. Able to grow faster since they don't have as much DNA to replicate with each cell cycle.
3. Able to combine with other haploid cells via fertilization.

In addition to cell division, another key stage in each life cycle is fertilization, or the fusion of two cells, which results in the formation of a diploid cell, the zygote.

We will now review the three major types of Eukaryotic life cycles (sporic, zygotic and gametic) in more detail.

Gametic Life Cycle

The gametic life cycle is the reproductive cycle found in animals and some protistans. The term gametic refers to the fact that gametes are the result of meiosis.

During the gametic life cycle a reproductive cell produces haploid gametes (sex cells such as egg and sperm) that combine to produce a zygote. The zygote grows by cell division and cell elongation to produce a multicellular diploid individual. In the gametic life cycle, the gametes are the only haploid stage found in the life cycle. The gametes (egg and sperm) are the only haploid cells produced.

Figure (PageIndex{1}). (CC BY-NC-SA)

Zygotic Life Cycle

The zygotic life cycle is the simplest sexual life cycle, common among fungi and protists. These organisms are haploid during most of their life cycle.

In the zygotic life cycle, the zygote is the only diploid phase. After fertilization the zygote undergoes meiosis to produce haploid cells. The cells undergo mitosis to either increase in number or grow into a haploid multicellular organism. Some haploid cells develop into gametes by mitosis.

Figure (PageIndex{2}). (CC BY-NC-SA)

Sporic Life Cycle

The sporic life cycle is common algae and plants. The term sporic refers to the fact that spores are the result of meiosis.

The sporic life cycle results from an alternation between a haploid and a diploid organism. Because of this, sometimes this cycle is referred to as the "alternation of generations". The diploid zygote first replicates by a series of mitotic divisions to form a multicellular diploid organism, known as a sporophyte. The sporophyte undergoes meiosis and produces haploid spores. These spores germinate and differentiate into haploid multicellular individuals known as gametophytes. The gametophyte produces eggs and sperm by mitosis. The zygote that results from syngamy of the gametes grows into the sporophyte by repeated mitotic divisions and the cycle continues.

Figure (PageIndex{3}). (CC BY-NC-SA)


Eukaryotic Life Cycles Tutorial by Dr. Katherine Harris is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

Funded by the U.S. Department of Education, Developing Hispanic Serving Institutions Program, #P031S090007.


Did meiosis evolve before sex and the evolution of eukaryotic life cycles?

Biologists have long theorized about the evolution of life cycles, meiosis, and sexual reproduction. We revisit these topics and propose that the fundamental difference between life cycles is where and when multicellularity is expressed. We develop a scenario to explain the evolutionary transition from the life cycle of a unicellular organism to one in which multicellularity is expressed in either the haploid or diploid phase, or both. We propose further that meiosis might have evolved as a mechanism to correct for spontaneous whole-genome duplication (auto-polyploidy) and thus before the evolution of sexual reproduction sensu stricto (i.e. the formation of a diploid zygote via the fusion of haploid gametes) in the major eukaryotic clades. In addition, we propose, as others have, that sexual reproduction, which predominates in all eukaryotic clades, has many different advantages among which is that it produces variability among offspring and thus reduces sibling competition.

Keywords: algae alternation of generations auto-polyploidy chiasmata embryophytes meiosis syngamy.


Contents

The study of reproduction and development in organisms was carried out by many botanists and zoologists.

Wilhelm Hofmeister demonstrated that alternation of generations is a feature that unites plants, and published this result in 1851 (see plant sexuality).

Some terms (haplobiont and diplobiont) used for the description of life cycles were proposed initially for algae by Nils Svedelius, and then became used for other organisms. [4] [5] Other terms (autogamy and gamontogamy) used in protist life cycles were introduced by Karl Gottlieb Grell. [6] The description of the complex life cycles of various organisms contributed to the disproof of the ideas of spontaneous generation in the 1840s and 1850s. [7]

A zygotic meiosis is a meiosis of a zygote immediately after karyogamy, which is the fusion of two cell nuclei. This way, the organism ends its diploid phase and produces several haploid cells. These cells divide mitotically to form either larger, multicellular individuals, or more haploid cells. Two opposite types of gametes (e.g., male and female) from these individuals or cells fuse to become a zygote.

In the whole cycle, zygotes are the only diploid cell mitosis occurs only in the haploid phase.

The individuals or cells as a result of mitosis are haplonts, hence this life cycle is also called haplontic life cycle. Haplonts are:

  • In archaeplastidans: some green algae (e.g., Chlamydomonas, Zygnema, Chara) [8]
  • In stramenopiles: some golden algae[8]
  • In alveolates: many dinoflagellates, e.g., Ceratium, Gymnodinium, some apicomplexans (e.g., Plasmodium) [9]
  • In rhizarians: some euglyphids, [10]ascetosporeans
  • In excavates: some parabasalids[11]
  • In amoebozoans: Dictyostelium[8]
  • In opisthokonts: most fungi (some chytrids, zygomycetes, some ascomycetes, basidiomycetes) [8][12] : 15

In gametic meiosis, instead of immediately dividing meiotically to produce haploid cells, the zygote divides mitotically to produce a multicellular diploid individual or a group of more unicellular diploid cells. Cells from the diploid individuals then undergo meiosis to produce haploid cells or gametes. Haploid cells may divide again (by mitosis) to form more haploid cells, as in many yeasts, but the haploid phase is not the predominant life cycle phase. In most diplonts, mitosis occurs only in the diploid phase, i.e. gametes usually form quickly and fuse to produce diploid zygotes.

In the whole cycle, gametes are usually the only haploid cells, and mitosis usually occurs only in the diploid phase.

The diploid multicellular individual is a diplont, hence a gametic meiosis is also called a diplontic life cycle. Diplonts are:

  • In archaeplastidans: some green algae (e.g., Cladophora glomerata, [13]Acetabularia[8] )
  • In stramenopiles: some brown algae (the Fucales, however, their life cycle can also be interpreted as strongly heteromorphic-diplohaplontic, with a highly reduced gametophyte phase, as in the flowering plants), [12] : 207 some xanthophytes (e.g., Vaucheria), [12] : 124 most diatoms, [11] some oomycetes (e.g., Saprolegnia, Plasmopara viticola), [8]opalines, [11] some "heliozoans" (e.g., Actinophrys, Actinosphaerium) [11][14]
  • In alveolates: ciliates[11]
  • In excavates: some parabasalids[11]
  • In opisthokonts: animals, some fungi (e.g., some ascomycetes) [8]

In sporic meiosis (also commonly known as intermediary meiosis), the zygote divides mitotically to produce a multicellular diploid sporophyte. The sporophyte creates spores via meiosis which also then divide mitotically producing haploid individuals called gametophytes. The gametophytes produce gametes via mitosis. In some plants the gametophyte is not only small-sized but also short-lived in other plants and many algae, the gametophyte is the "dominant" stage of the life cycle.

  • In archaeplastidans: red algae (which have two sporophyte generations), some green algae (e.g., Ulva), land plants[8]
  • In stramenopiles: most brown algae[8]
  • In rhizarians: many foraminiferans, [11]plasmodiophoromycetes[8]
  • In amoebozoa: myxogastrids
  • In opisthokonts: some fungi (some chytrids, some ascomycetes like the brewer's yeast) [8]
  • Other eukaryotes: haptophytes[11]

Some animals have a sex-determination system called haplodiploid, but this is not related to the haplodiplontic life cycle.

Some red algae (such as Bonnemaisonia [15] and Lemanea) and green algae (such as Prasiola) have vegetative meiosis, also called somatic meiosis, which is a rare phenomenon. [12] : 82 Vegetative meiosis can occur in haplodiplontic and also in diplontic life cycles. The gametophytes remain attached to and part of the sporophyte. Vegetative (non-reproductive) diploid cells undergo meiosis, generating vegetative haploid cells. These undergo many mitosis, and produces gametes.

A different phenomenon, called vegetative diploidization, a type of apomixis, occurs in some brown algae (e.g., Elachista stellaris). [16] Cells in a haploid part of the plant spontaneously duplicate their chromosomes to produce diploid tissue.

Parasites depend on the exploitation of one or more hosts. Those that must infect more than one host species to complete their life cycles are said to have complex or indirect life cycles. Dirofilaria immitis, or the heartworm, has an indirect life cycle, for example. The microfilariae must first be ingested by a female mosquito, where it develops into the infective larval stage. The mosquito then bites an animal and transmits the infective larvae into the animal, where they migrate to the pulmonary artery and mature into adults. [17]

Those parasites that infect a single species have direct life cycles. An example of a parasite with a direct life cycle is Ancylostoma caninum, or the canine hookworm. They develop to the infective larval stage in the environment, then penetrate the skin of the dog directly and mature to adults in the small intestine. [18]

If a parasite has to infect a given host in order to complete its life cycle, then it is said to be an obligate parasite of that host sometimes, infection is facultative—the parasite can survive and complete its life cycle without infecting that particular host species. Parasites sometimes infect hosts in which they cannot complete their life cycles these are accidental hosts.

A host in which parasites reproduce sexually is known as the definitive, final or primary host. In intermediate hosts, parasites either do not reproduce or do so asexually, but the parasite always develops to a new stage in this type of host. In some cases a parasite will infect a host, but not undergo any development, these hosts are known as paratenic [19] or transport hosts. The paratenic host can be useful in raising the chance that the parasite will be transmitted to the definitive host. For example, the cat lungworm (Aelurostrongylus abstrusus) uses a slug or snail as an intermediate host the first stage larva enters the mollusk and develops to the third stage larva, which is infectious to the definitive host—the cat. If a mouse eats the slug, the third stage larva will enter the mouse's tissues, but will not undergo any development.

The primitive type of life cycle probably had haploid individuals with asexual reproduction. [11] Bacteria and archaea exhibit a life cycle like this, and some eukaryotes apparently do too (e.g., Cryptophyta, Choanoflagellata, many Euglenozoa, many Amoebozoa, some red algae, some green algae, the imperfect fungi, some rotifers and many other groups, not necessarily haploid). [20] However, these eukaryotes probably are not primitively asexual, but have lost their sexual reproduction, or it just was not observed yet. [21] [22] Many eukaryotes (including animals and plants) exhibit asexual reproduction, which may be facultative or obligate in the life cycle, with sexual reproduction occurring more or less frequently. [23]

Individual organisms participating in a biological life cycle ordinarily age and die, while cells from these organisms that connect successive life cycle generations (germ line cells and their descendants) are potentially immortal. The basis for this difference is a fundamental problem in biology. The Russian biologist and historian Zhores A. Medvedev [24] considered that the accuracy of genome replicative and other synthetic systems alone cannot explain the immortality of germ lines. Rather Medvedev thought that known features of the biochemistry and genetics of sexual reproduction indicate the presence of unique information maintenance and restoration processes at the gametogenesis stage of the biological life cycle. In particular, Medvedev considered that the most important opportunities for information maintenance of germ cells are created by recombination during meiosis and DNA repair he saw these as processes within the germ line cells that were capable of restoring the integrity of DNA and chromosomes from the types of damage that cause irreversible ageing in non-germ line cells, e.g. somatic cells.

The ancestry of each present day cell presumably traces back, in an unbroken lineage for over 3 billion years to the origin of life. It is not actually cells that are immortal but multi-generational cell lineages. [25] The immortality of a cell lineage depends on the maintenance of cell division potential. This potential may be lost in any particular lineage because of cell damage, terminal differentiation as occurs in nerve cells, or programmed cell death (apoptosis) during development. Maintenance of cell division potential of the biological life cycle over successive generations depends on the avoidance and the accurate repair of cellular damage, particularly DNA damage. In sexual organisms, continuity of the germline over successive cell cycle generations depends on the effectiveness of processes for avoiding DNA damage and repairing those DNA damages that do occur. Sexual processes in eukaryotes, as well as in prokaryotes, provide an opportunity for effective repair of DNA damages in the germ line by homologous recombination. [25] [26]


Eukaryotic Cell (With Diagram)

A eukaryote cell is the one which has an organised nucleus and several membrane covered cell organelles. Except monera, the cells of all other kingdoms have eukaryotic organisation. Cell wall is present in cells of plants, fungi and some protists.

It is absent in animal cells and some protists. Wall less cells are generally irregular. Otherwise, internal structure of all cells is somewhat similar. A cell is an organised mass of protoplasm sur­rounded by a protective and selectively permeable membrane. Protoplasm of a cell is called protoplast.

It is made up of cytoplasm, nucleus and vacuoles. Initially, cytoplasm was thought to have simple organisation. Electron microscope has shown that cytoplasm has a complex organisation formed of cytoplasmic matrix and cell organelles. There are cytoskeletal structures which not only provide movement to cytoplasm but also other locomotory activities.

Genetic material or DNA is organised into chromosomes and chromatin. Plant cells possess cell wall, plastids and large central vacuole. They are absent in animal cells. Animal cells possess centrioles that are absent in plant cells.

A plant cell consists of cell wall and protoplast. Cell wall is absent in animal cells. Protoplast denotes the whole of protoplasm present in a cell.

It is differentiated into plasma membrane (= plasma lemma or cell membrane), cytoplasm, nucleus and vacuoles. Cyto­plasm is distinguishable into cytoplasmic matrix and organelles. Cytoplasmic matrix is also called hyaloplasm. It is a polyphasic colloidal system which exists in two states, sol and gel.

The gel form usually occurs near the plasma membrane. This region is sometimes called ectoplast in contrast to sol region known as endoplast. Ectoplast is firmer. It is quite conspicuous on the free sides of the cells. In protozoans, ectoplast is prominent on all sides.

Cytoplasmic matrix is generally in perpetual motion. The phenomenon is called cyclosis, cytoplasmic or protoplasmic streaming. Cytoplasmic matrix occupies the volume of the cells. It is the major arena of cellular activities that keep a cell in the living state.

In the cytoplasmic matrix are embedded a large number of cell organelles or organised protoplasmic subunits having specific functions.

They are endoplasmic reticulum, plastids, mitochondria, ribosomes, Golgi bodies, centrioles (central apparatus, centrosome), lysos­omes, sphaerosomes, peroxisomes, glyoxysomes, vacuoles, microtubules, microfilaments, etc. Some of them have membrane covering while others are without the same.

Doubling membrane covering occurs around plastids and mitochondria. Single membrane covering is found over endoplasmic reticulum, Golgi apparatus, lysosomes, sphaerosomes, peroxisomes, glyoxysomes and vacuole.

Organelles without a membrane covering are ribosomes, micro­tubules, microfilaments and centrosomes or centrioles (in animal cells). Ribosomes are found in both prokaryotes and eukaryotes. In eukaryote cells they occur in cytoplasmic matrix, over rough endoplasmic reticulum, inside plastids (found only in plants and some protists and mitochondria).

Cell inclusions include starch grains, glycogen granules, fat droplets, aleurone grains, excretory or secretory products and crystals. Nucleus is also embedded in the cytoplasmic matrix. It is surrounded by a double membrane envelope and contains nucleoplasm, one or more nucleoli and chromatin having DNA. DNA is the genetic material.


Contents

The study of reproduction and development in organisms was carried out by many botanists and zoologists.

Wilhelm Hofmeister demonstrated that alternation of generations is a feature that unites plants, and published this result in 1851 (see plant sexuality).

Some terms (haplobiont and diplobiont) used for the description of life cycles were proposed initially for algae by Nils Svedelius, and then became used for other organisms. [4] [5] Other terms (autogamy and gamontogamy) used in protist life cycles were introduced by Karl Gottlieb Grell. [6] The description of the complex life cycles of various organisms contributed to the disproof of the ideas of spontaneous generation in the 1840s and 1850s. [7]

A zygotic meiosis is a meiosis of a zygote immediately after karyogamy, which is the fusion of two cell nuclei. This way, the organism ends its diploid phase and produces several haploid cells. These cells divide mitotically to form either larger, multicellular individuals, or more haploid cells. Two opposite types of gametes (e.g., male and female) from these individuals or cells fuse to become a zygote.

In the whole cycle, zygotes are the only diploid cell mitosis occurs only in the haploid phase.

The individuals or cells as a result of mitosis are haplonts, hence this life cycle is also called haplontic life cycle. Haplonts are:

  • In archaeplastidans: some green algae (e.g., Chlamydomonas, Zygnema, Chara) [8]
  • In stramenopiles: some golden algae[8]
  • In alveolates: many dinoflagellates, e.g., Ceratium, Gymnodinium, some apicomplexans (e.g., Plasmodium) [9]
  • In rhizarians: some euglyphids, [10]ascetosporeans
  • In excavates: some parabasalids[11]
  • In amoebozoans: Dictyostelium[8]
  • In opisthokonts: most fungi (some chytrids, zygomycetes, some ascomycetes, basidiomycetes) [8][12] : 15

In gametic meiosis, instead of immediately dividing meiotically to produce haploid cells, the zygote divides mitotically to produce a multicellular diploid individual or a group of more unicellular diploid cells. Cells from the diploid individuals then undergo meiosis to produce haploid cells or gametes. Haploid cells may divide again (by mitosis) to form more haploid cells, as in many yeasts, but the haploid phase is not the predominant life cycle phase. In most diplonts, mitosis occurs only in the diploid phase, i.e. gametes usually form quickly and fuse to produce diploid zygotes.

In the whole cycle, gametes are usually the only haploid cells, and mitosis usually occurs only in the diploid phase.

The diploid multicellular individual is a diplont, hence a gametic meiosis is also called a diplontic life cycle. Diplonts are:

  • In archaeplastidans: some green algae (e.g., Cladophora glomerata, [13]Acetabularia[8] )
  • In stramenopiles: some brown algae (the Fucales, however, their life cycle can also be interpreted as strongly heteromorphic-diplohaplontic, with a highly reduced gametophyte phase, as in the flowering plants), [12] : 207 some xanthophytes (e.g., Vaucheria), [12] : 124 most diatoms, [11] some oomycetes (e.g., Saprolegnia, Plasmopara viticola), [8]opalines, [11] some "heliozoans" (e.g., Actinophrys, Actinosphaerium) [11][14]
  • In alveolates: ciliates[11]
  • In excavates: some parabasalids[11]
  • In opisthokonts: animals, some fungi (e.g., some ascomycetes) [8]

In sporic meiosis (also commonly known as intermediary meiosis), the zygote divides mitotically to produce a multicellular diploid sporophyte. The sporophyte creates spores via meiosis which also then divide mitotically producing haploid individuals called gametophytes. The gametophytes produce gametes via mitosis. In some plants the gametophyte is not only small-sized but also short-lived in other plants and many algae, the gametophyte is the "dominant" stage of the life cycle.

  • In archaeplastidans: red algae (which have two sporophyte generations), some green algae (e.g., Ulva), land plants[8]
  • In stramenopiles: most brown algae[8]
  • In rhizarians: many foraminiferans, [11]plasmodiophoromycetes[8]
  • In amoebozoa: myxogastrids
  • In opisthokonts: some fungi (some chytrids, some ascomycetes like the brewer's yeast) [8]
  • Other eukaryotes: haptophytes[11]

Some animals have a sex-determination system called haplodiploid, but this is not related to the haplodiplontic life cycle.

Some red algae (such as Bonnemaisonia [15] and Lemanea) and green algae (such as Prasiola) have vegetative meiosis, also called somatic meiosis, which is a rare phenomenon. [12] : 82 Vegetative meiosis can occur in haplodiplontic and also in diplontic life cycles. The gametophytes remain attached to and part of the sporophyte. Vegetative (non-reproductive) diploid cells undergo meiosis, generating vegetative haploid cells. These undergo many mitosis, and produces gametes.

A different phenomenon, called vegetative diploidization, a type of apomixis, occurs in some brown algae (e.g., Elachista stellaris). [16] Cells in a haploid part of the plant spontaneously duplicate their chromosomes to produce diploid tissue.

Parasites depend on the exploitation of one or more hosts. Those that must infect more than one host species to complete their life cycles are said to have complex or indirect life cycles. Dirofilaria immitis, or the heartworm, has an indirect life cycle, for example. The microfilariae must first be ingested by a female mosquito, where it develops into the infective larval stage. The mosquito then bites an animal and transmits the infective larvae into the animal, where they migrate to the pulmonary artery and mature into adults. [17]

Those parasites that infect a single species have direct life cycles. An example of a parasite with a direct life cycle is Ancylostoma caninum, or the canine hookworm. They develop to the infective larval stage in the environment, then penetrate the skin of the dog directly and mature to adults in the small intestine. [18]

If a parasite has to infect a given host in order to complete its life cycle, then it is said to be an obligate parasite of that host sometimes, infection is facultative—the parasite can survive and complete its life cycle without infecting that particular host species. Parasites sometimes infect hosts in which they cannot complete their life cycles these are accidental hosts.

A host in which parasites reproduce sexually is known as the definitive, final or primary host. In intermediate hosts, parasites either do not reproduce or do so asexually, but the parasite always develops to a new stage in this type of host. In some cases a parasite will infect a host, but not undergo any development, these hosts are known as paratenic [19] or transport hosts. The paratenic host can be useful in raising the chance that the parasite will be transmitted to the definitive host. For example, the cat lungworm (Aelurostrongylus abstrusus) uses a slug or snail as an intermediate host the first stage larva enters the mollusk and develops to the third stage larva, which is infectious to the definitive host—the cat. If a mouse eats the slug, the third stage larva will enter the mouse's tissues, but will not undergo any development.

The primitive type of life cycle probably had haploid individuals with asexual reproduction. [11] Bacteria and archaea exhibit a life cycle like this, and some eukaryotes apparently do too (e.g., Cryptophyta, Choanoflagellata, many Euglenozoa, many Amoebozoa, some red algae, some green algae, the imperfect fungi, some rotifers and many other groups, not necessarily haploid). [20] However, these eukaryotes probably are not primitively asexual, but have lost their sexual reproduction, or it just was not observed yet. [21] [22] Many eukaryotes (including animals and plants) exhibit asexual reproduction, which may be facultative or obligate in the life cycle, with sexual reproduction occurring more or less frequently. [23]

Individual organisms participating in a biological life cycle ordinarily age and die, while cells from these organisms that connect successive life cycle generations (germ line cells and their descendants) are potentially immortal. The basis for this difference is a fundamental problem in biology. The Russian biologist and historian Zhores A. Medvedev [24] considered that the accuracy of genome replicative and other synthetic systems alone cannot explain the immortality of germ lines. Rather Medvedev thought that known features of the biochemistry and genetics of sexual reproduction indicate the presence of unique information maintenance and restoration processes at the gametogenesis stage of the biological life cycle. In particular, Medvedev considered that the most important opportunities for information maintenance of germ cells are created by recombination during meiosis and DNA repair he saw these as processes within the germ line cells that were capable of restoring the integrity of DNA and chromosomes from the types of damage that cause irreversible ageing in non-germ line cells, e.g. somatic cells.

The ancestry of each present day cell presumably traces back, in an unbroken lineage for over 3 billion years to the origin of life. It is not actually cells that are immortal but multi-generational cell lineages. [25] The immortality of a cell lineage depends on the maintenance of cell division potential. This potential may be lost in any particular lineage because of cell damage, terminal differentiation as occurs in nerve cells, or programmed cell death (apoptosis) during development. Maintenance of cell division potential of the biological life cycle over successive generations depends on the avoidance and the accurate repair of cellular damage, particularly DNA damage. In sexual organisms, continuity of the germline over successive cell cycle generations depends on the effectiveness of processes for avoiding DNA damage and repairing those DNA damages that do occur. Sexual processes in eukaryotes, as well as in prokaryotes, provide an opportunity for effective repair of DNA damages in the germ line by homologous recombination. [25] [26]


Fungal Diversity

The kingdom Fungi contains four major divisions that were established according to their mode of sexual reproduction. Polyphyletic, unrelated fungi that reproduce without a sexual cycle, are placed for convenience in a fifth division, and a sixth major fungal group that does not fit well with any of the previous five has recently been described. Not all mycologists agree with this scheme. Rapid advances in molecular biology and the sequencing of 18S rRNA (a component of ribosomes) continue to reveal new and different relationships between the various categories of fungi.

The traditional divisions of Fungi are the Chytridiomycota (chytrids), the Zygomycota (conjugated fungi), the Ascomycota (sac fungi), and the Basidiomycota (club fungi). An older classification scheme grouped fungi that strictly use asexual reproduction into Deuteromycota, a group that is no longer in use. The Glomeromycota belong to a newly described group ([Figure 5]).

Figure 5: Divisions of fungi include (a) chytrids, (b) conjugated fungi, (c) sac fungi, and (d) club fungi. (credit a: modification of work by USDA APHIS PPQ credit c: modification of work by “icelight”/Flickr credit d: modification of work by Cory Zanker.)


Wanted: loriciferans, dead or alive

The current debate should focus interest not solely on the old Wild West dead-or-alive issue but also on the rich biology in these habitats and the importance of obtaining new samples from the sediments in question and similar habitats. Indeed, there is no debate about the ability of unicellular eukaryotes to survive in the anoxic brine, nor is there debate about animals living on the margins of the anoxic zone [3]. The issue is the ability of metazoans (multicellular eukaryotes) to survive in the strictly anaeorbic zone. Ideally, one would like to see some evidence for actively transcribed genes in loriciferans from these habitats. That would also tell us a lot about how they are growing with respect to core carbon and energy metabolism. In particular, one would want to know whether these animals harbor and express any of the genes that protists use to survive in anaerobic environments, such as [FeFe]-hydrogenase, pyruvate:ferredoxin oxidoreductase, bifunctional alcohol dehydrogenase E (ADHE), acetyl-CoA synthase (ADP forming), and the like [4], or whether they have some other means of surviving without oxygen. It is perhaps more likely that they use strategies more similar to those found in the anaerobic mitochondria of parasitic animals, for example, malate dismutation with the involvement of rhodoquinone [4].

As a long shot alternative, if the animals are alive, it is even imaginable that they have acquired genes via lateral gene transfer (LGT) for a new strategy to survive anoxia. Indeed, some camps argue that all eukaryotes are ancestrally strict aerobes and that the ability of eukaryotes to survive anoxia is always the result of lateral gene transfer [9]. We do not agree with that view, mainly for three reasons. First, the eukaryotic anaerobes studied so far always have the same basic carbon and energy metabolic backbone [4] and if LGT was behind eukaryote anaerobiosis, then eukaryotic anaerobes should be as physiologically diverse as prokaryotic anaerobes, which is definitely not the case energy metabolism based on sulfate reduction [10], which is lacking in eukaryotes, is a strong case in point. Second, the Earth sciences tell us that anaerobic habitats are ancient and that aerobic habitats are recent [8]. So, if anything, we should be seeing LGT as a means of improving mitochondrial function in aerobic habitats. For example, aerobic methane oxidation is a very widespread form of energy metabolism in prokaryotes but we don’t see eukaryotes that have acquired genes to do that rather, eukaryotes possess one ancestrally present stock of enzymes [4]. Third, it is often proposed that one lineage of eukaryotes acquires one or the other anaerobic enzyme via LGT from prokaryotes and then passes it around via eukaryote to eukaryote LGT in order to account for the monophyly of the eukaryote enzymes involved. That idea has been specifically tested at the whole-genome level, and rejected, whereby the “patchy gene distributions” that are often seen as the hallmark of LGT are actually better explained by differential loss than they are by LGT [11].

Of course it might also turn out that the loriciferans from the habitats in question do not show vital signs of gene expression. It might be that they are dead, not alive. There is only one way to find out: biologists will have to go back out to those deep environments and get new samples.


TCA cycle signalling and the evolution of eukaryotes

A major question remaining in the field of evolutionary biology is how prokaryotic organisms made the leap to complex eukaryotic life. The prevailing theory depicts the origin of eukaryotic cell complexity as emerging from the symbiosis between an α-proteobacterium, the ancestor of present-day mitochondria, and an archaeal host (endosymbiont theory). A primary contribution of mitochondria to eukaryogenesis has been attributed to the mitochondrial genome, which enabled the successful internalisation of bioenergetic membranes and facilitated remarkable genome expansion. It has also been postulated that a key contribution of the archaeal host during eukaryogenesis was in providing 'archaeal histones' that would enable compaction and regulation of an expanded genome. Yet, how the communication between the host and the symbiont evolved is unclear. Here, we propose an evolutionary concept in which mitochondrial TCA cycle signalling was also a crucial player during eukaryogenesis enabling the dynamic control of an expanded genome via regulation of DNA and histone modifications. Furthermore, we discuss how TCA cycle remodelling is a common evolutionary strategy invoked by eukaryotic organisms to coordinate stress responses and gene expression programmes, with a particular focus on the TCA cycle-derived metabolite itaconate.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Overview of all 8 chemical reactions of the TCA cycle…

Figure 2. The endosymbiont and entangle-engulf-endogenize (E3)…

Figure 2. The endosymbiont and entangle-engulf-endogenize (E3) hypothesis

Overview of the endosymbiont/E3 hypothesis. (A) Lokiarchaeon…

Figure 3. The acquisition of mitochondria supported…

Figure 3. The acquisition of mitochondria supported the emergence of multicellularity

Heterotrophic prokaryotes with low…

Figure 4. An evolutionary timeline of eukaryotic…

Figure 4. An evolutionary timeline of eukaryotic cell development

In our proposed timeline, the TCA…

Figure 5. How TCA cycle signalling may…

Figure 5. How TCA cycle signalling may have contributed to eukaryogenesis by acting as a…


Contents

The eukaryotic cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis and cytokinesis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's nucleus divides, and cytokinesis, in which the cell's cytoplasm divides forming two daughter cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.

State Phase Abbreviation Description
Resting Gap 0 G0 A phase where the cell has left the cycle and has stopped dividing.
Interphase Gap 1 G1 Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis.
Synthesis S DNA replication occurs during this phase.
Gap 2 G2 During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.
Cell division Mitosis M Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.

After cell division, each of the daughter cells begin the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.

G0 phase (quiescence) Edit

G0 is a resting phase where the cell has left the cycle and has stopped dividing. The cell cycle starts with this phase. Non-proliferative (non-dividing) cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Some cells enter the G0 phase semi-permanently and are considered post-mitotic, e.g., some liver, kidney, and stomach cells. Many cells do not enter G0 and continue to divide throughout an organism's life, e.g., epithelial cells.

The word "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Cellular senescence occurs in response to DNA damage and external stress and usually constitutes an arrest in G1. Cellular senescence may make a cell's progeny nonviable it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis.

Interphase Edit

Interphase is a series of changes that takes place in a newly formed cell and its nucleus before it becomes capable of division again. It is also called preparatory phase or intermitosis. Typically interphase lasts for at least 91% of the total time required for the cell cycle.

Interphase proceeds in three stages, G1, S, and G2, followed by the cycle of mitosis and cytokinesis. The cell's nuclear DNA contents are duplicated during S phase.

G1 phase (First growth phase or Post mitotic gap phase) Edit

The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis, is called G1 (G indicating gap). It is also called the growth phase. During this phase, the biosynthetic activities of the cell, which are considerably slowed down during M phase, resume at a high rate. The duration of G1 is highly variable, even among different cells of the same species. [3] In this phase, the cell increases its supply of proteins, increases the number of organelles (such as mitochondria, ribosomes), and grows in size. In G1 phase, a cell has three options.

  • To continue cell cycle and enter S phase
  • Stop cell cycle and enter G0 phase for undergoing differentiation.
  • Become arrested in G1 phase hence it may enter G0 phase or re-enter cell cycle.

The deciding point is called check point (Restriction point). This check point is called the restriction point or START and is regulated by G1/S cyclins, which cause transition from G1 to S phase. Passage through the G1 check point commits the cell to division.

S phase (DNA replication) Edit

The ensuing S phase starts when DNA synthesis commences when it is complete, all of the chromosomes have been replicated, i.e., each chromosome consists of two sister chromatids. Thus, during this phase, the amount of DNA in the cell has doubled, though the ploidy and number of chromosomes are unchanged. Rates of RNA transcription and protein synthesis are very low during this phase. An exception to this is histone production, most of which occurs during the S phase. [4] [5] [6]

G2 phase (growth) Edit

G2 phase occurs after DNA replication and is a period of protein synthesis and rapid cell growth to prepare the cell for mitosis. During this phase microtubules begin to reorganize to form a spindle (preprophase). Before proceeding to mitotic phase, cells must be checked at the G2 checkpoint for any DNA damage within the chromosomes. The G2 checkpoint is mainly regulated by the tumor protein p53. If the DNA is damaged, p53 will either repair the DNA or trigger the apoptosis of the cell. If p53 is dysfunctional or mutated, cells with damaged DNA may continue through the cell cycle, leading to the development of cancer.

Mitotic phase (chromosome separation) Edit

The relatively brief M phase consists of nuclear division (karyokinesis). It is a relatively short period of the cell cycle. M phase is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These phases are sequentially known as:

Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two nuclei. [7] During the process of mitosis the pairs of chromosomes condense and attach to microtubules that pull the sister chromatids to opposite sides of the cell. [8]

Mitosis occurs exclusively in eukaryotic cells, but occurs in different ways in different species. For example, animal cells undergo an "open" mitosis, where the nuclear envelope breaks down before the chromosomes separate, while fungi such as Aspergillus nidulans and Saccharomyces cerevisiae (yeast) undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus. [9]

Cytokinesis phase (separation of all cell components) Edit

Mitosis is immediately followed by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle.

Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei in a process called endoreplication. This occurs most notably among the fungi and slime molds, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development. [10] Errors in mitosis can result in cell death through apoptosis or cause mutations that may lead to cancer.

Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.

Role of cyclins and CDKs Edit

Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle. [11] Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules. [12] Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general, more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae [13] genetic nomenclature in yeast dubs many of these genes cdc (for "cell division cycle") followed by an identifying number, e.g. cdc25 or cdc20.

Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals. [14]

General mechanism of cyclin-CDK interaction Edit

Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome. However, results from a recent study of E2F transcriptional dynamics at the single-cell level argue that the role of G1 cyclin-CDK activities, in particular cyclin D-CDK4/6, is to tune the timing rather than the commitment of cell cycle entry. [15]

Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes is also deleterious to the daughter cells.

Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed. [16]

Specific action of cyclin-CDK complexes Edit

Cyclin D is the first cyclin produced in the cells that enter the cell cycle, in response to extracellular signals (e.g. growth factors). Cyclin D levels stay low in resting cells that are not proliferating. Additionally, CDK4/6 and CDK2 are also inactive because CDK4/6 are bound by INK4 family members (e.g., p16), limiting kinase activity. Meanwhile, CDK2 complexes are inhibited by the CIP/KIP proteins such as p21 and p27, [17] When it is time for a cell to enter the cell cycle, which is triggered by a mitogenic stimuli, levels of cyclin D increase. In response to this trigger, cyclin D binds to existing CDK4/6, forming the active cyclin D-CDK4/6 complex. Cyclin D-CDK4/6 complexes in turn mono-phosphorylates the retinoblastoma susceptibility protein (Rb) to pRb. The un-phosphorylated Rb tumour suppressor functions in inducing cell cycle exit and maintaining G0 arrest (senescence). [18]

In the last few decades, a model has been widely accepted whereby pRB proteins are inactivated by cyclin D-Cdk4/6-mediated phosphorylation. Rb has 14+ potential phosphorylation sites. Cyclin D-Cdk 4/6 progressively phosphorylates Rb to hyperphosphorylated state, which triggers dissociation of pRB–E2F complexes, thereby inducing G1/S cell cycle gene expression and progression into S phase. [19]

However, scientific observations from a recent study show that Rb is present in three types of isoforms: (1) un-phosphorylated Rb in G0 state (2) mono-phosphorylated Rb, also referred to as "hypo-phosphorylated' or 'partially' phosphorylated Rb in early G1 state and (3) inactive hyper-phosphorylated Rb in late G1 state. [20] [21] [22] In early G1 cells, mono-phosphorylated Rb exits as 14 different isoforms, one of each has distinct E2F binding affinity. [22] Rb has been found to associate with hundreds of different proteins [23] and the idea that different mono-phosphorylated Rb isoforms have different protein partners was very appealing. [24] A recent report confirmed that mono-phosphorylation controls Rb's association with other proteins and generates functional distinct forms of Rb. [25] All different mono-phosphorylated Rb isoforms inhibit E2F transcriptional program and are able to arrest cells in G1-phase. Importantly, different mono-phosphorylated forms of RB have distinct transcriptional outputs that are extended beyond E2F regulation. [25]

In general, the binding of pRb to E2F inhibits the E2F target gene expression of certain G1/S and S transition genes including E-type cyclins. The partial phosphorylation of RB de-represses the Rb-mediated suppression of E2F target gene expression, begins the expression of cyclin E. The molecular mechanism that causes the cell switched to cyclin E activation is currently not known, but as cyclin E levels rise, the active cyclin E-CDK2 complex is formed, bringing Rb to be inactivated by hyper-phosphorylation. [22] Hyperphosphorylated Rb is completely dissociated from E2F, enabling further expression of a wide range of E2F target genes are required for driving cells to proceed into S phase [1]. Recently, it has been identified that cyclin D-Cdk4/6 binds to a C-terminal alpha-helix region of Rb that is only distinguishable to cyclin D rather than other cyclins, cyclin E, A and B. [26] This observation based on the structural analysis of Rb phosphorylation supports that Rb is phosphorylated in a different level through multiple Cyclin-Cdk complexes. This also makes feasible the current model of a simultaneous switch-like inactivation of all mono-phosphorylated Rb isoforms through one type of Rb hyper-phosphorylation mechanism. In addition, mutational analysis of the cyclin D- Cdk 4/6 specific Rb C-terminal helix shows that disruptions of cyclin D-Cdk 4/6 binding to Rb prevents Rb phosphorylation, arrests cells in G1, and bolsters Rb's functions in tumor suppressor. [26] This cyclin-Cdk driven cell cycle transitional mechanism governs a cell committed to the cell cycle that allows cell proliferation. A cancerous cell growth often accompanies with deregulation of Cyclin D-Cdk 4/6 activity.

The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S, which initiates the G2/M transition). [27] Cyclin B-cdk1 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis. [14] A quantitative study of E2F transcriptional dynamics at the single-cell level by using engineered fluorescent reporter cells provided a quantitative framework for understanding the control logic of cell cycle entry, challenging the canonical textbook model. Genes that regulate the amplitude of E2F accumulation, such as Myc, determine the commitment in cell cycle and S phase entry. G1 cyclin-CDK activities are not the driver of cell cycle entry. Instead, they primarily tune the timing of E2F increase, thereby modulating the pace of cell cycle progression. [15]

Inhibitors Edit

Endogenous Edit

Two families of genes, the cip/kip (CDK interacting protein/Kinase inhibitory protein) family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) family, prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.

The cip/kip family includes the genes p21, p27 and p57. They halt the cell cycle in G1 phase by binding to and inactivating cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor β (TGF β), a growth inhibitor.

The INK4a/ARF family includes p16 INK4a , which binds to CDK4 and arrests the cell cycle in G1 phase, and p14 ARF which prevents p53 degradation.

Synthetic Edit

Synthetic inhibitors of Cdc25 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents. [28]

Many human cancers possess the hyper-activated Cdk 4/6 activities. [29] Given the observations of cyclin D-Cdk 4/6 functions, inhibition of Cdk 4/6 should result in preventing a malignant tumor from proliferating. Consequently, scientists have tried to invent the synthetic Cdk4/6 inhibitor as Cdk4/6 has been characterized to be a therapeutic target for anti-tumor effectiveness. Three Cdk4/6 inhibitors - palbociclib, ribociclib, and abemaciclib - currently received FDA approval for clinical use to treat advanced-stage or metastatic, hormone-receptor-positive (HR-positive, HR+), HER2-negative (HER2-) breast cancer. [30] [31] For example, palbociclib is an orally active CDK4/6 inhibitor which has demonstrated improved outcomes for ER-positive/HER2-negative advanced breast cancer. The main side effect is neutropenia which can be managed by dose reduction. [32]

Cdk4/6 targeted therapy will only treat cancer types where Rb is expressed. Cancer cells with loss of Rb have primary resistance to Cdk4/6 inhibitors.

Transcriptional regulatory network Edit

Current evidence suggests that a semi-autonomous transcriptional network acts in concert with the CDK-cyclin machinery to regulate the cell cycle. Several gene expression studies in Saccharomyces cerevisiae have identified 800–1200 genes that change expression over the course of the cell cycle. [13] [33] [34] They are transcribed at high levels at specific points in the cell cycle, and remain at lower levels throughout the rest of the cycle. While the set of identified genes differs between studies due to the computational methods and criteria used to identify them, each study indicates that a large portion of yeast genes are temporally regulated. [35]

Many periodically expressed genes are driven by transcription factors that are also periodically expressed. One screen of single-gene knockouts identified 48 transcription factors (about 20% of all non-essential transcription factors) that show cell cycle progression defects. [36] Genome-wide studies using high throughput technologies have identified the transcription factors that bind to the promoters of yeast genes, and correlating these findings with temporal expression patterns have allowed the identification of transcription factors that drive phase-specific gene expression. [33] [37] The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK-autonomous network of these transcription factors is sufficient to produce steady-state oscillations in gene expression). [34] [38]

Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando et al. used microarrays to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type cells and cells lacking all S-phase and mitotic cyclins (clb1,2,3,4,5,6). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin-deficient cells at the same time as in the wild type cells, despite the fact that the cyclin-deficient cells arrest at the border between G1 and S phase. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK-cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK-cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events. [34] Other work indicates that phosphorylation, a post-translational modification, of cell cycle transcription factors by Cdk1 may alter the localization or activity of the transcription factors in order to tightly control timing of target genes. [36] [39] [40]

While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK-cyclin machinery operates independently in the early embryonic cell cycle. Before the midblastula transition, zygotic transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded mRNA. [41]

DNA replication and DNA replication origin activity Edit

Analyses of synchronized cultures of Saccharomyces cerevisiae under conditions that prevent DNA replication initiation without delaying cell cycle progression showed that origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes. [42] This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression, [43] [44] [45] and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.

Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle. [46] Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met. Checkpoints typically consist of a network of regulatory proteins that monitor and dictate the progression of the cell through the different stages of the cell cycle.

It is estimated that in normal human cells about 1% of single-strand DNA damages are converted to about 50 endogenous DNA double-strand breaks per cell per cell cycle. [47] Although such double-strand breaks are usually repaired with high fidelity, errors in their repair are considered to contribute significantly to the rate of cancer in humans. [47]

There are several checkpoints to ensure that damaged or incomplete DNA is not passed on to daughter cells. Three main checkpoints exist: the G1/S checkpoint, the G2/M checkpoint and the metaphase (mitotic) checkpoint. Another checkpoint is the Go checkpoint, in which the cells are checked for maturity. If the cells fail to pass this checkpoint by not being ready yet, they will be discarded from dividing.

G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point. [14] This is where the cell checks whether it has enough raw materials to fully replicate its DNA (nucleotide bases, DNA synthase, chromatin, etc.). An unhealthy or malnourished cell will get stuck at this checkpoint.

The G2/M checkpoint is where the cell ensures that it has enough cytoplasm and phospholipids for two daughter cells. But sometimes more importantly, it checks to see if it is the right time to replicate. There are some situations where many cells need to all replicate simultaneously (for example, a growing embryo should have a symmetric cell distribution until it reaches the mid-blastula transition). This is done by controlling the G2/M checkpoint.

The metaphase checkpoint is a fairly minor checkpoint, in that once a cell is in metaphase, it has committed to undergoing mitosis. However that's not to say it isn't important. In this checkpoint, the cell checks to ensure that the spindle has formed and that all of the chromosomes are aligned at the spindle equator before anaphase begins. [48]

While these are the three "main" checkpoints, not all cells have to pass through each of these checkpoints in this order to replicate. Many types of cancer are caused by mutations that allow the cells to speed through the various checkpoints or even skip them altogether. Going from S to M to S phase almost consecutively. Because these cells have lost their checkpoints, any DNA mutations that may have occurred are disregarded and passed on to the daughter cells. This is one reason why cancer cells have a tendency to exponentially accrue mutations. Aside from cancer cells, many fully differentiated cell types no longer replicate so they leave the cell cycle and stay in G0 until their death. Thus removing the need for cellular checkpoints. An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint.

Checkpoint regulation plays an important role in an organism's development. In sexual reproduction, when egg fertilization occurs, when the sperm binds to the egg, it releases signalling factors that notify the egg that it has been fertilized. Among other things, this induces the now fertilized oocyte to return from its previously dormant, G0, state back into the cell cycle and on to mitotic replication and division.

p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints. In addition to p53, checkpoint regulators are being heavily researched for their roles in cancer growth and proliferation.

Pioneering work by Atsushi Miyawaki and coworkers developed the fluorescent ubiquitination-based cell cycle indicator (FUCCI), which enables fluorescence imaging of the cell cycle. Originally, a green fluorescent protein, mAG, was fused to hGem(1/110) and an orange fluorescent protein (mKO2) was fused to hCdt1(30/120). Note, these fusions are fragments that contain a nuclear localization signal and ubiquitination sites for degradation, but are not functional proteins. The green fluorescent protein is made during the S, G2, or M phase and degraded during the G0 or G1 phase, while the orange fluorescent protein is made during the G0 or G1 phase and destroyed during the S, G2, or M phase. [49] A far-red and near-infrared FUCCI was developed using a cyanobacteria-derived fluorescent protein (smURFP) and a bacteriophytochrome-derived fluorescent protein (movie found at this link). [50]

A disregulation of the cell cycle components may lead to tumor formation. [51] As mentioned above, when some genes like the cell cycle inhibitors, RB, p53 etc. mutate, they may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumors is much higher than that in normal tissue. [ citation needed ] Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.

The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs or radiation. This fact is made use of in cancer treatment by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle. [14]

The fastest cycling mammalian cells in culture, crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. M and S do not vary much.

In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S phase.

For cells with a longer cell cycle time and a significantly long G1 phase, there is a second peak of resistance late in G1.

The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural substances that protect cells from radiation damage and tend to be at their highest levels in S and at their lowest near mitosis.

Homologous recombination (HR) is an accurate process for repairing DNA double-strand breaks. HR is nearly absent in G1 phase, is most active in S phase, and declines in G2/M. [52] Non-homologous end joining, a less accurate and more mutagenic process for repairing double strand breaks, is active throughout the cell cycle.


Coupling of S Phase to M Phase

The G2 checkpoint prevents the initiation of mitosis prior to the completion of S phase, thereby ensuring that incompletely replicated DNA is not distributed to daughter cells. It is equally important to ensure that the genome is replicated only once per cell cycle. Thus, once DNA has been replicated, control mechanisms must exist to prevent initiation of a new S phase prior to mitosis. These controls prevent cells in G2 from reentering S phase and block the initiation of another round of DNA replication until after mitosis, at which point the cell has entered the G1 phase of the next cell cycle.

Initial insights into this dependence of S phase on M phase came from cell fusion experiments of Potu Rao and Robert Johnson in 1970 (Figure 14.10). These investigators isolated cells in different phases of the cycle and then fused these cells to each other to form cell hybrids. When G1 cells were fused with S phase cells, the G1 nucleus immediately began to synthesize DNA. Thus, the cytoplasm of S phase cells contained factors that initiated DNA synthesis in the G1 nucleus. Fusing G2 cells with S phase cells, however, yielded a quite different result: The G2 nucleus was unable to initiate DNA synthesis even in the presence of an S phase cytoplasm. It thus appeared that DNA synthesis in the G2 nucleus was prevented by a mechanism that blocked rereplication of the genome until after mitosis had taken place.

Figure 14.10

Cell fusion experiments demonstrating the dependence of S phase on M phase. Cells in S phase were fused either to cells in G1 or to cells in G2. When G1 cells were fused with S phase cells, the G1 nucleus immediately began to replicate DNA. In contrast, (more. )

The molecular mechanism that restricts DNA replication to once per cell cycle involves the action of a family of proteins (called MCM proteins) that bind to replication origins together with the origin replication complex (ORC) proteins (see Figure 5.17). The MCM proteins act as “licensing factors” that allow replication to initiate (Figure 14.11). Their binding to DNA is regulated during the cell cycle such that the MCM proteins are only able to bind to replication origins during G1, allowing DNA replication to initiate when the cell enters S phase. Once initiation has occurred, however, the MCM proteins are displaced from the origin, so replication cannot initiate again until the cell passes through mitosis and enters G1 phase of the next cell cycle.

Figure 14.11

Restriction of DNA replication. DNA replication is restricted to once per cell cycle by MCM proteins that bind to origins of replication together with ORC (origin replication complex) proteins and are required for the initiation of DNA replication. MCM (more. )

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.


Watch the video: 1 1 Τα μόρια της ζωής (November 2022).