Endoreduplication
Encyclopedia
Endoreplication is replication of the nuclear genome
in the absence of cell division
, which leads to elevated nuclear gene
content and polyploidy
. Endoreplication can be understood simply as a variant form of the mitotic cell cycle
(G1-S-G2-M) in which mitosis
is aborted prior to cytokinesis
or circumvented entirely, due in part to modulation of cyclin-dependent kinase
(CDK) activity. Examples of endoreplication characterized in arthropod
, mammalian, and plant
species
suggest that it is a universal developmental mechanism responsible for the differentiation and morphogenesis
of cell types that fulfill an array of biological functions. While endoreplication is often limited to specific cell types in animals, it is considerably more widespread in plants, such that polyploidy can be detected in the majority of plant tissues.
content, but the manner in which the genetic material is configured varies depending on whether mitotic events are allowed to occur. Endocycling is a form of endoreplication in which the cell largely avoids mitosis and duplicated chromatids remain physically associated. Repeated rounds of endocycling can lead to the production of polytene chromosomes in which sister chromatids are tightly configured in parallel arrays. In contrast, endomitosis is a form of endoreplication in which cells undergo aspects of mitosis but fail to execute telophase
and/or cytokinesis
. Duplicated chromosomes produced by endomitosis exist as discrete units in a single polyploid nucleus
or may be packaged into separate nuclei, depending on the phase at which mitosis is aborted. In certain instances (e.g. trophoblast giant cells), the distinction between endocycling and endomitosis is clouded, as the cell undergoes early mitotic events such as chromosome condensation that tend to diminish the physical association among homologous chromosomes. It should also be noted that endocycling does not always involve replication of the entire genome, and that certain regions are often replicated more frequently than others.
Cell/Organism Size:
Cell ploidy
often correlates with cell size, and in some instances, disruption of endoreplication results in diminished cell and tissue size suggesting that endoreplication may serve as a mechanism for tissue growth. Relative to mitosis, endoreplication does not require cytoskeletal rearrangement or the production of new cell membrane
and it often occurs in cells that have already differentiated. As such it may represent an energetically efficient alternative to cell proliferation among differentiated cell types that can no longer afford to undergo mitosis. While evidence establishing a connection between ploidy and tissue size is prevalent in the literature, contrary examples also exist.
Cell Differentiation:
In developing plant tissues the transition from mitosis to endoreplication often coincides with cell differentiation and morphogenesis
. However it remains to be determined whether endoreplication and polypoidy contribute to cell differentiation or vice versa. Interestingly, targeted inhibition of endoreplication in trichome
progenitors results in the production of multicelluar trichomes that exhibit relatively normal morphology, but ultimately dedifferentiate and undergo absorption into the leaf epidermis. This result suggests that endoreplication and polyploidy may be required for the maintenance of cell identity.
Oogenesis and Embryonic Development:
Endoreplication is commonly observed in cell
s responsible for the nourishment and protection of oocytes and embryos. It has been suggested that increased gene copy number might allow for the mass production of proteins required to meet the metabolic demands of embryogenesis
and early development. Consistent with this notion, mutation of the Myc
oncogene
in Drosophila
follicle cells results in reduced endoreplication and abortive oogenesis
. However, reduction of endoreplication in maize endosperm
has limited effect on the accumulation of starch
and storage proteins, suggesting that the nutritional requirements of the developing embryo may involve the nucleotides that comprise the polyploid genome rather than the proteins it encodes.
Buffering the Genome:
Another intriguing hypothesis is that endoreplication buffers against DNA damage and mutation
because it provides extra copies of important genes
. However, this notion is purely speculative and there is limited evidence to the contrary. For example, analysis of polyploid yeast
strains suggests that they are more sensitive to radiation
than diploid strains.
Stress Response:
Research in plants suggests that endoreplication may also play a role in modulating stress responses. By manipulating expression of E2f
e (a repressor of endocycling in plants), researchers were able to demonstrate that increased cell ploidy lessens the negative impact of drought stress on leaf size. Given that the sessile lifestyle of plants necessitates a capacity to adapt to environmental conditions, it is appealing to speculate that widespread polyploidization contributes to their developmental plasticity
follicle cells and is activated by Notch signaling
. Entry into endocycles involves modulation of mitotic and S-phase cyclin-dependent kinase
(CDK) activity. Inhibition of M-phase CDK activity is accomplished via transcriptional activation of Cdh
/fzr and repression of the G2-M regulator string/cdc25
. Cdh/fzr is responsible for activation of the anaphase-promoting complex
(APC) and subsequent proteolysis
of the mitotic cyclins. String/cdc25 is a phosphatase
that stimulates mitotic cyclin-CDK complex activity. Upregulation of S-phase CDK activity is accomplished via transcriptional repression of the inhibitory kinase
dacapo. Together, these changes allow for the circumvention of mitotic entry, progression through G1
, and entry into S-phase. The induction of endomitosis in mammalian megakaryocytes involves activation of the c-mpl receptor by the thrombopoietin
(TPO) cytokine
and is mediated by ERK1/2 signaling. As with Drosophila follicle cells, endoreplication in megakaryocytes results from activation of S-phase cyclin-CDK complexes and inhibition of mitotic cyclin-CDK activity.
Entry into S-phase during endoreplication (and mitosis) is regulated through the formation of a prereplicative complex (pre-RC) at replication origins, followed by recruitment and activation of the DNA replication
machinery. In the context of endoreplication these events are facilitated by an oscillation in cyclin E
-Cdk2 activity. Cyclin E-Cdk2 activity drives the recruitment and activation of the replication machinery, but it also inhibits pre-RC formation, presumably to ensure that only one round of replication occurs per cycle. Failure to maintain control over pre-RC formation at replication origins results in a phenomenon known as “rereplication” which is common in cancer cells. The mechanism by which cyclin E-Cdk2 inhibits pre-RC formation involves downregulation of APC
-Cdh1
-mediated proteolysis and accumulation of the protein Geminin
, which is responsible for sequestration of the pre-RC component Cdt1.
Oscillations in Cyclin E
-Cdk2 activity are modulated via transcriptional and post-transcriptional mechanisms. Expression of cyclin E is activated by E2F
transcription factors that were shown to be required for endoreplication. Recent work suggests that observed oscillations in E2F and cyclin E protein levels result from a negative-feedback loop involving Cul4-dependent ubiquitination and degradation of E2F. Post-transcriptional regulation of cyclin E-Cdk2 activity involves Ago/Fbw7-mediated proteolytic degradation of cyclin E and direct inhibition by factors such as Dacapo and p57.
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
in the absence of cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, which leads to elevated nuclear gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
content and polyploidy
Polyploidy
Polyploid is a term used to describe cells and organisms containing more than two paired sets of chromosomes. Most eukaryotic species are diploid, meaning they have two sets of chromosomes — one set inherited from each parent. However polyploidy is found in some organisms and is especially common...
. Endoreplication can be understood simply as a variant form of the mitotic cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
(G1-S-G2-M) in which mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
is aborted prior to cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
or circumvented entirely, due in part to modulation of cyclin-dependent kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(CDK) activity. Examples of endoreplication characterized in arthropod
Arthropod
An arthropod is an invertebrate animal having an exoskeleton , a segmented body, and jointed appendages. Arthropods are members of the phylum Arthropoda , and include the insects, arachnids, crustaceans, and others...
, mammalian, and plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
suggest that it is a universal developmental mechanism responsible for the differentiation and morphogenesis
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
of cell types that fulfill an array of biological functions. While endoreplication is often limited to specific cell types in animals, it is considerably more widespread in plants, such that polyploidy can be detected in the majority of plant tissues.
Examples in nature
Endoreplicating cell types that have been studied extensively in model organisms| Organism | Cell Type | Biological Function | Citation |
|---|---|---|---|
| fly Fly True flies are insects of the order Diptera . They possess a pair of wings on the mesothorax and a pair of halteres, derived from the hind wings, on the metathorax... |
larval tissues (incl. salivary glands) | secretion Secretion Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product... , embryogenesis Embryogenesis Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote... |
|
| fly Fly True flies are insects of the order Diptera . They possess a pair of wings on the mesothorax and a pair of halteres, derived from the hind wings, on the metathorax... |
ovarian follicle Ovarian follicle Ovarian follicles are the basic units of female reproductive biology, each of which is composed of roughly spherical aggregations of cells found in the ovary. They contain a single oocyte . These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single... , nurse cells |
nourishment, protection of oocytes | |
| rodent Rodent Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing.... |
megakaryocyte Megakaryocyte The megakaryocyte is a bone marrow cell responsible for the production of blood thrombocytes , which are necessary for normal blood clotting... |
platelet Platelet Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days... formation |
|
| rodent Rodent Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing.... |
trophoblast giant cell | placental development, nourishment of embryo Embryo An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination... |
|
| plant Plant Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or... |
trichome Trichome Trichomes are fine outgrowths or appendages on plants and certain protists. These are of diverse structure and function. Examples are hairs, glandular hairs, scales, and papillae.- Algal trichomes :... |
defense from herbivory, homeostasis Homeostasis Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH... |
|
| plant Plant Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or... |
leaf Leaf A leaf is an organ of a vascular plant, as defined in botanical terms, and in particular in plant morphology. Foliage is a mass noun that refers to leaves as a feature of plants.... epidermal Epidermis (botany) The epidermis is a single-layered group of cells that covers plants' leaves, flowers, roots and stems. It forms a boundary between the plant and the external environment. The epidermis serves several functions, it protects against water loss, regulates gas exchange, secretes metabolic compounds,... cell Cell (biology) The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos.... |
leaf size, structure | |
| plant Plant Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or... |
endosperm Endosperm Endosperm is the tissue produced inside the seeds of most flowering plants around the time of fertilization. It surrounds the embryo and provides nutrition in the form of starch, though it can also contain oils and protein. This makes endosperm an important source of nutrition in human diet... |
nourishment of embryo Embryo An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination... |
|
| nematode Nematode The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode... |
hypodermis Hypodermis The hypodermis, also called the hypoderm, subcutaneous tissue, or superficial fascia is the lowermost layer of the integumentary system in vertebrates. Types of cells that are found in the hypodermis are fibroblasts, adipose cells, and macrophages... |
secretion Secretion Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product... , body size |
Endocycling vs. endomitosis
Endoreplication typically results in elevated cellular DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
content, but the manner in which the genetic material is configured varies depending on whether mitotic events are allowed to occur. Endocycling is a form of endoreplication in which the cell largely avoids mitosis and duplicated chromatids remain physically associated. Repeated rounds of endocycling can lead to the production of polytene chromosomes in which sister chromatids are tightly configured in parallel arrays. In contrast, endomitosis is a form of endoreplication in which cells undergo aspects of mitosis but fail to execute telophase
Telophase
Telophase from the ancient Greek "τελος" and "φασις" , is a stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase events are reversed. Two daughter nuclei form in the cell. The nuclear envelopes of the daughter cells are formed from the...
and/or cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
. Duplicated chromosomes produced by endomitosis exist as discrete units in a single polyploid nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
or may be packaged into separate nuclei, depending on the phase at which mitosis is aborted. In certain instances (e.g. trophoblast giant cells), the distinction between endocycling and endomitosis is clouded, as the cell undergoes early mitotic events such as chromosome condensation that tend to diminish the physical association among homologous chromosomes. It should also be noted that endocycling does not always involve replication of the entire genome, and that certain regions are often replicated more frequently than others.
Biological significance
Based on the wide array of cell types in which endoreplication occurs, a variety of hypotheses have been generated to explain the functional importance of this phenomenon. Unfortunately, experimental evidence to support these conclusions is somewhat limited:Cell/Organism Size:
Cell ploidy
Ploidy
Ploidy is the number of sets of chromosomes in a biological cell.Human sex cells have one complete set of chromosomes from the male or female parent. Sex cells, also called gametes, combine to produce somatic cells. Somatic cells, therefore, have twice as many chromosomes. The haploid number is...
often correlates with cell size, and in some instances, disruption of endoreplication results in diminished cell and tissue size suggesting that endoreplication may serve as a mechanism for tissue growth. Relative to mitosis, endoreplication does not require cytoskeletal rearrangement or the production of new cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
and it often occurs in cells that have already differentiated. As such it may represent an energetically efficient alternative to cell proliferation among differentiated cell types that can no longer afford to undergo mitosis. While evidence establishing a connection between ploidy and tissue size is prevalent in the literature, contrary examples also exist.
Cell Differentiation:
In developing plant tissues the transition from mitosis to endoreplication often coincides with cell differentiation and morphogenesis
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
. However it remains to be determined whether endoreplication and polypoidy contribute to cell differentiation or vice versa. Interestingly, targeted inhibition of endoreplication in trichome
Trichome
Trichomes are fine outgrowths or appendages on plants and certain protists. These are of diverse structure and function. Examples are hairs, glandular hairs, scales, and papillae.- Algal trichomes :...
progenitors results in the production of multicelluar trichomes that exhibit relatively normal morphology, but ultimately dedifferentiate and undergo absorption into the leaf epidermis. This result suggests that endoreplication and polyploidy may be required for the maintenance of cell identity.
Oogenesis and Embryonic Development:
Endoreplication is commonly observed in cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s responsible for the nourishment and protection of oocytes and embryos. It has been suggested that increased gene copy number might allow for the mass production of proteins required to meet the metabolic demands of embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
and early development. Consistent with this notion, mutation of the Myc
Myc
Myc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...
oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
in Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
follicle cells results in reduced endoreplication and abortive oogenesis
Oogenesis
Oogenesis, ovogenesis or oögenesis is the creation of an ovum . It is the female form of gametogenesis. The male equivalent is spermatogenesis...
. However, reduction of endoreplication in maize endosperm
Endosperm
Endosperm is the tissue produced inside the seeds of most flowering plants around the time of fertilization. It surrounds the embryo and provides nutrition in the form of starch, though it can also contain oils and protein. This makes endosperm an important source of nutrition in human diet...
has limited effect on the accumulation of starch
Starch
Starch or amylum is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. This polysaccharide is produced by all green plants as an energy store...
and storage proteins, suggesting that the nutritional requirements of the developing embryo may involve the nucleotides that comprise the polyploid genome rather than the proteins it encodes.
Buffering the Genome:
Another intriguing hypothesis is that endoreplication buffers against DNA damage and mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
because it provides extra copies of important genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
. However, this notion is purely speculative and there is limited evidence to the contrary. For example, analysis of polyploid yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
strains suggests that they are more sensitive to radiation
Radiation
In physics, radiation is a process in which energetic particles or energetic waves travel through a medium or space. There are two distinct types of radiation; ionizing and non-ionizing...
than diploid strains.
Stress Response:
Research in plants suggests that endoreplication may also play a role in modulating stress responses. By manipulating expression of E2f
E2F
E2F is a group of genes that codifies a family of transcription factors in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells...
e (a repressor of endocycling in plants), researchers were able to demonstrate that increased cell ploidy lessens the negative impact of drought stress on leaf size. Given that the sessile lifestyle of plants necessitates a capacity to adapt to environmental conditions, it is appealing to speculate that widespread polyploidization contributes to their developmental plasticity
Genetic control of endoreplication
The best-studied example of a mitosis-to-endocycle transition occurs in DrosophilaDrosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
follicle cells and is activated by Notch signaling
Notch signaling
The notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms.Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass...
. Entry into endocycles involves modulation of mitotic and S-phase cyclin-dependent kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(CDK) activity. Inhibition of M-phase CDK activity is accomplished via transcriptional activation of Cdh
CDH
CDH may refer to:* Campbell's dwarf hamster* The Central DuPage Hospital in DuPage County, Illinois, U.S.A.* Centre Démocrate Humaniste, a Belgian political party* Chronic daily headache...
/fzr and repression of the G2-M regulator string/cdc25
Cdc25
Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle".Dual-specificity phosphatases are considered a sub-class...
. Cdh/fzr is responsible for activation of the anaphase-promoting complex
Anaphase-promoting complex
Anaphase-Promoting Complex, also called cyclosome , is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin and RING subunit much like SCF...
(APC) and subsequent proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
of the mitotic cyclins. String/cdc25 is a phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
that stimulates mitotic cyclin-CDK complex activity. Upregulation of S-phase CDK activity is accomplished via transcriptional repression of the inhibitory kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
dacapo. Together, these changes allow for the circumvention of mitotic entry, progression through G1
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
, and entry into S-phase. The induction of endomitosis in mammalian megakaryocytes involves activation of the c-mpl receptor by the thrombopoietin
Thrombopoietin
Thrombopoietin also known as megakaryocyte growth and development factor is a protein that in humans is encoded by the THPO gene....
(TPO) cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
and is mediated by ERK1/2 signaling. As with Drosophila follicle cells, endoreplication in megakaryocytes results from activation of S-phase cyclin-CDK complexes and inhibition of mitotic cyclin-CDK activity.
Entry into S-phase during endoreplication (and mitosis) is regulated through the formation of a prereplicative complex (pre-RC) at replication origins, followed by recruitment and activation of the DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
machinery. In the context of endoreplication these events are facilitated by an oscillation in cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
-Cdk2 activity. Cyclin E-Cdk2 activity drives the recruitment and activation of the replication machinery, but it also inhibits pre-RC formation, presumably to ensure that only one round of replication occurs per cycle. Failure to maintain control over pre-RC formation at replication origins results in a phenomenon known as “rereplication” which is common in cancer cells. The mechanism by which cyclin E-Cdk2 inhibits pre-RC formation involves downregulation of APC
APC
-Biology:* Adenomatous polyposis coli, a type of colon cancer caused by a defect APC-protein due to mutations in the APC-gene* Antigen-presenting cell in medicine/immunology* Activated protein C, an anti-coagulant and anti-inflammatory protein...
-Cdh1
CDH1
CDH1 may refer to:* Huntsville/Deerhurst Resort Airport* CDH1 classical cadherin from the cadherin superfamily* APC/C activator protein CDH1 Cell-cycle regulated activator of the anaphase-promoting complex/cyclosome...
-mediated proteolysis and accumulation of the protein Geminin
Geminin
Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene.Geminin is a nuclear protein that is present in most eukaryotics and highly conserved across species...
, which is responsible for sequestration of the pre-RC component Cdt1.
Oscillations in Cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
-Cdk2 activity are modulated via transcriptional and post-transcriptional mechanisms. Expression of cyclin E is activated by E2F
E2F
E2F is a group of genes that codifies a family of transcription factors in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells...
transcription factors that were shown to be required for endoreplication. Recent work suggests that observed oscillations in E2F and cyclin E protein levels result from a negative-feedback loop involving Cul4-dependent ubiquitination and degradation of E2F. Post-transcriptional regulation of cyclin E-Cdk2 activity involves Ago/Fbw7-mediated proteolytic degradation of cyclin E and direct inhibition by factors such as Dacapo and p57.