endoreplication
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Endoreduplication (also referred to as endoreplication or endocycling) is replication of the nuclear
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
in the absence of mitosis, which leads to elevated nuclear
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
content and
polyploidy Polyploidy is a condition in which the biological cell, cells of an organism have more than one pair of (Homologous chromosome, homologous) chromosomes. Most species whose cells have Cell nucleus, nuclei (eukaryotes) are diploid, meaning they ha ...
. Endoreplication can be understood simply as a variant form of the mitotic
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
(G1-S-G2-M) in which mitosis is circumvented entirely, due to modulation of cyclin-dependent kinase (CDK) activity. Examples of endoreplication characterized in
arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and cuticle made of chiti ...
,
mammalian Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
, and
plant Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclu ...
species In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
suggest that it is a universal developmental mechanism responsible for the differentiation and
morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
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
polyploid Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei ( eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contain ...
y can be detected in the majority of plant tissues.


Examples in nature

Endoreplicating cell types that have been studied extensively in
model organisms A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the working ...


Endoreplication, endomitosis and polytenization

Endoreplication, endomitosis and polytenization are three somewhat different processes resulting in polyploidization of a cell in a regulated manner. In endoreplication cells skip
M phase The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
completely, resulting in a mononucleated
polyploid Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei ( eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contain ...
cell. Endomitosis is a type of cell cycle variation where mitosis is initiated, but some of the processes are not completed. Depending on how far the cell progresses through mitosis, this will give rise to a mononucleated or binucleated polyploid cell. Polytenization arises with under- or overamplification of some genomic regions, creating
polytene chromosome Polytene chromosomes are large chromosomes which have thousands of DNA strands. They provide a high level of function in certain tissues such as salivary glands of insects. Polytene chromosomes were first reported by E.G.Balbiani in 1881. P ...
s.


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 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 The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...
rearrangement or the production of new
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
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 (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
. However it remains to be determined whether endoreplication and
polyploidy Polyploidy is a condition in which the biological cell, cells of an organism have more than one pair of (Homologous chromosome, homologous) chromosomes. Most species whose cells have Cell nucleus, nuclei (eukaryotes) are diploid, meaning they ha ...
contribute to cell differentiation or vice versa. Targeted inhibition of endoreplication in
trichome Trichomes (); ) are fine outgrowths or appendages on plants, algae, lichens, and certain protists. They are of diverse structure and function. Examples are hairs, glandular hairs, scales, and papillae. A covering of any kind of hair on a p ...
progenitors results in the production of multicellular trichomes that exhibit relatively normal morphology, but ultimately dedifferentiate and undergo absorption into the
leaf epidermis The epidermis (from the Greek ''ἐπιδερμίς'', meaning "over-skin") is a single layer of cells that covers the leaves, flowers, roots and stems of plants. It forms a boundary between the plant and the external environment. The 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 most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
s responsible for the nourishment and protection of
oocytes An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female g ...
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 ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
in ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
'' 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 Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules with ...
that comprise the
polyploid Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei ( eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contain ...
genome rather than the proteins it encodes.


Buffering the genome

Another hypothesis is that endoreplication buffers against
DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
and
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
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 Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constit ...
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 E2fe (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 ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
'' follicle cells and is activated by
Notch signaling The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transme ...
. Entry into endocycles involves modulation of
mitotic In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...
and
S-phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
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 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 or genes such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell divis ...
. Cdh/fzr is responsible for activation of the
anaphase-promoting complex Anaphase-promoting complex (also called the cyclosome or APC/C) 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 cull ...
(APC) and subsequent proteolysis of the
mitotic In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...
cyclins Cyclin is a family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle. Etymology Cyclins were originally di ...
. 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 S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
. The induction of endomitosis in mammalian
megakaryocytes A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...
involves activation of the c-mpl receptor by the
thrombopoietin Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene. Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
(TPO)
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
and is mediated by ERK1/2 signaling. As with Drosophila follicle cells, endoreplication in megakaryocytes results from activation of
S-phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
cyclin-CDK complexes and inhibition of mitotic cyclin-CDK activity. Entry into
S-phase S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
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 In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
machinery. In the context of endoreplication these events are facilitated by an oscillation in
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 of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27K ...
-
Cdk2 Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the ''CDK2'' gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein ...
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 Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the ''GMNN'' gene. A nuclear protein present in most eukaryotes and highly conserved across species, numerous functions have been elucidated for geminin inc ...
, which is responsible for sequestration of the pre-RC component
Cdt1 CDT1 (Chromatin licensing and DNA replication factor 1) is a protein that in humans is encoded by the ''CDT1'' gene. It is a licensing factor that functions to limit DNA from replicating more than once per cell cycle. Role in pre-replication com ...
. Oscillations in
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 of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27K ...
-
Cdk2 Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the ''CDK2'' gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein ...
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 Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by other ...
involving Cul4-dependent
ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
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. True endomitosis in the anther tapetum of the liliaceous plant Eremurus is described. The nuclear membrane does not disappear, but during metaphase the chromosomes are condensed, often considerably more than in normal mitosis. When the pollen mother cells (PMCs) go through the last premeiotic mitosis, the tapetal cells have one diploid nucleus which divides while the cell remains undivided. The two diploid nuclei may undergo an endomitosis and the resulting tetraploid nuclei a second endomitosis. An alternative pathway is an ordinary mitosis-again without cell division instead of one of the endomitotic cycles. The cytological picture in the tapetum is further complicated by restitution in anaphase and fusion of metaphase and anaphase groups during mitosis, processes which could give rise to cells with one, two, or three nuclei, instead of the expected two or four. No sign of the so-called "inhibited" mitosis is seen in these tapetal cells. When the PMCs are in leptotene-zygotene, very few tapetal nuclei are in endomitosis. When the PMCs have reached diplotene, almost 100% of cells which are not in interphase show an endomitotic stage.


Endoreplication and oncogenesis

Polyploidy and aneuploidy are common phenomena in cancer cells. Given that oncogenesis and endoreplication likely involve subversion of common cell cycle regulatory mechanisms, a thorough understanding of endoreplication may provide important insights for cancer biology.


Premeiotic endomitosis in unisexual vertebrates

The unisexual salamanders (genus '' Ambystoma'') are the oldest known unisexual vertebrate lineage, having arisen about 5 million years ago. In these polyploid unisexual females, an extra premeiotic endomitotic replication of the genome, doubles the number of chromosomes. As a result, the mature eggs that are produced subsequent to the two meiotic divisions have the same ploidy as the somatic cells of the adult female salamander. Synapsis and recombination during meiotic prophase I in these unisexual females is thought to ordinarily occur between identical sister chromosomes and occasionally between homologous chromosomes. Thus little, if any, genetic variation is produced. Recombination between homeologous chromosomes occurs rarely, if at all. Since production of genetic variation is weak, at best, it is unlikely to provide a benefit sufficient to account for the maintenance of meiosis for millions of years. Perhaps the efficient recombinational repair of DNA damages at each generation provided by meiosis has been a sufficient advantage to maintain meiosis.


References

{{reflist, colwidth=30em Genetics Cell biology Cell cycle