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{{short description|Replication of the nuclear genome without mitosis}}{{cs1 config|name-list-style=vanc}}
'''Endoreduplication''' (also referred to as '''endoreplication''' or '''endocycling''') is replication of the nuclear [[genome]] in the absence of [[mitosis]], which leads to elevated nuclear [[gene]] content and [[polyploidy]]. Endoreduplication can be understood simply as a variant form of the mitotic [[cell cycle]] (G1-S-G2-M) in which [[mitosis]] is circumvented entirely, due to modulation of [[cyclin-dependent kinase]] (CDK) activity.<ref name=Edgarone>{{cite journal | doi = 10.1016/S0092-8674(01)00334-8 | title = Endoreplication cell cycles: more for less | journal = Cell | volume = 105 | issue = 3 | pages = 297–306 | year = 2001 | author1 = Edgar BA | author2 = Orr-Weaver TL | pmid = 11348589 | doi-access = free }}</ref><ref name=Leeone>{{cite journal | doi = 10.1101/gad.1829209 | title = Endoreplication: polyploidy with purpose | journal = Genes & Development | volume = 23 | issue = 21 | pages = 2461–77 | year = 2008 | author1 = Lee HO | author2 = Davidson JM | author3 = Duronio RJ | pmid = 19884253 | pmc = 2779750 }}</ref><ref name=":0">{{Cite journal|last1=Edgar|first1=Bruce A.|last2=Zielke|first2=Norman|last3=Gutierrez|first3=Crisanto|date=2014-02-21|title=Endocycles: a recurrent evolutionary innovation for post-mitotic cell growth|journal=Nature Reviews Molecular Cell Biology|language=en|volume=15|issue=3|pages=197–210|doi=10.1038/nrm3756|pmid=24556841|s2cid=641731|issn=1471-0080}}</ref><ref name=":1">{{Cite journal|last=Orr-Weaver|first=Terry L.|title=When bigger is better: the role of polyploidy in organogenesis|journal=Trends in Genetics|volume=31|issue=6|pages=307–315|doi=10.1016/j.tig.2015.03.011|pmid=25921783|pmc=4537166|year=2015}}</ref> Examples of endoreduplication characterised 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.<ref name=Edgarone/><ref name=Leeone/> While endoreduplication is often limited to specific cell types in animals, it is considerably more widespread in plants, such that [[polyploid]]y can be detected in the majority of plant tissues.<ref name=Galbraithone>{{cite journal | doi = 10.1104/pp.96.3.985 | title = Systemic Endopolyploidy in Arabidopsis thaliana | journal = Plant Physiology | volume = 96 | issue = 3 | pages = 985–9 | year = 1991 | author1 = Galbraith DW | author2 = Harkins KR | author3 = Knapp S| pmid = 16668285 | pmc = 1080875 }}</ref> Polyploidy and aneuploidy are common phenomena in cancer cells.<ref name="Storchovaone">{{cite journal |author1=Storchova Z |author2=Pellman D |year=2004 |title=From polyploidy to aneuploidy, genome instability and cancer |journal=Nature Reviews Molecular Cell Biology |volume=5 |issue=1 |pages=45–54 |doi=10.1038/nrm1276 |pmid=14708009 |s2cid=11985415}}</ref> Given that oncogenesis and endoreduplication likely involve subversion of common cell cycle regulatory mechanisms, a thorough understanding of endoreduplication may provide important insights for cancer biology.

==Examples in nature==
Endoreduplicating cell types that have been studied extensively in [[model organisms]]
{| class="wikitable"
|-
!Organism
!Name
!Cell type
!Biological function
!Citation
|-
| style="text-align:center;"| [[fly]]
| rowspan="2" |''Drosophilia Melanogaster''
| [[larval]] tissues (incl. [[salivary glands]])
| [[secretion]], [[embryogenesis]]
| <ref name=Hammondone>{{cite journal | doi = 10.1007/BF00328223 | title = Control of DNA replication and spatial distribution of defined DNA sequences in salivary gland cells of ''Drosophila melanogaster'' | journal = Chromosoma | volume = 91 | issue = 3–4 | pages = 279–286 | year = 1985 | author1 = Hammond MP | author2 = Laird CD | pmid = 3920018 | s2cid = 1515555 }}</ref>
|-
| style="text-align:center;"| [[fly]]
| [[ovarian follicle]], [[nurse cells]]
| nourishment, protection of [[oocytes]]
| <ref name=Hammondtwo>{{cite journal | doi = 10.1007/BF00328222 | title = Chromosome structure and DNA replication in nurse and follicle cells of ''Drosophila melanogaster'' | journal = Chromosoma | volume = 91 | issue = 3–4 | pages = 267–278 | year = 1985 | author1 = Hammond MP | author2 = Laird CD | pmid = 3920017 | s2cid = 7919061 }}</ref>
|-
| style="text-align:center;"| [[rodent]]
|
| [[megakaryocyte]]
| [[platelet]] formation
| <ref name="Ravidone">{{cite journal |last1=Ravid |first1=K |author-link1=Katya Ravid |last2=Lu |first2=J |last3=Zimmet |first3=JM |last4=Jones |first4=MR |year=2002 |title=Roads to polyploidy: The megakaryocyte example |journal=Journal of Cellular Physiology |volume=190 |issue=1 |pages=7–20 |doi=10.1002/jcp.10035 |pmid=11807806 |s2cid=37297740}}</ref>
|-
| style="text-align:center;"| [[rodent]]
|
|[[hepatocyte]]
|[[Regeneration (biology)|regeneration]]
|<ref>{{Cite journal|last1=Wang|first1=Min-Jun|last2=Chen|first2=Fei|last3=Lau|first3=Joseph T. Y.|last4=Hu|first4=Yi-Ping|date=2017-05-18|title=Hepatocyte polyploidization and its association with pathophysiological processes|journal=Cell Death & Disease|language=en|volume=8|issue=5|pages=e2805|doi=10.1038/cddis.2017.167|pmid=28518148|pmc=5520697}}</ref>
|-
| style="text-align:center;"| [[rodent]]
|
| [[trophoblast giant cell]]
| [[placental development]], nourishment of [[embryo]]
| <ref name=Crossone>{{cite journal | doi = 10.1016/j.placenta.2005.01.015 | title = How to make a placenta: Mechanisms of trophoblast cell differentiation in mice-a review | journal = Placenta | volume = 26 | pages = S3–9 | year = 2005 | author1 = Cross JC | pmid = 15837063 }}</ref>
|-
| style="text-align:center;"| [[plant]]
| rowspan="3" |''Arabidopsis Thaliana''
| [[trichome]]
| defense from [[herbivory]], [[homeostasis]]
| <ref name=Hulskampone>{{cite book | doi = 10.1016/S0074-7696(08)61053-0 | title = Pattern Formation and Cell Differentiation: Trichomes in Arabidopsis as a Genetic Model System | volume = 186 | pages = 147–178 | year = 1999 | author1 = Hulskamp M | author2 = Schnittger A | author3 = Folkers U | pmid = 9770299 | series = International Review of Cytology | isbn = 978-0-12-364590-6 }}</ref>
|-
| style="text-align:center;"| [[plant]]
| [[leaf]] [[epidermis (botany)|epidermal]] [[cell (biology)|cell]]
| leaf size, structure
| <ref name=Melaragnoone>{{cite journal | doi = 10.1105/tpc.5.11.1661 | pmid = 12271050 | title = Relationship between endopolyploidy and cell size in epidermal tissue of ''Arabidopsis'' | jstor = 3869747 | journal = The Plant Cell | volume = 5 | issue = 11 | pages = 1661–8 | year = 1993 | author1 = Melaragno JE | author2 = Mehrotra B | author3 = Coleman AW | author3-link = Annette W. Coleman | pmc = 160394 }}</ref>
|-
| style="text-align:center;"| [[plant]]
| [[endosperm]]
| nourishment of [[embryo]]
| <ref name=Sabellione>{{cite journal | doi = 10.1104/pp.108.129437 | title = The Development of Endosperm in Grasses | journal = Plant Physiology | volume = 149 | issue = 1 | pages = 14–26 | year = 2009 | author1 = Sabelli PA | author2 = Larkins BA | pmid = 19126691 | pmc = 2613697 }}</ref>
|-
| style="text-align:center;"| [[nematode]]
| rowspan="2" |''Caenorhabditis elegans''
| [[hypodermis]]
| [[secretion]], [[body size]]
| <ref name=Flemmingone>{{cite journal | doi = 10.1073/pnas.97.10.5285 | title = Somatic polyploidization and cellular proliferation drive body size evolution in nematodes | journal = PNAS | volume = 97 | issue = 10 | pages = 5285–90 | year = 2000 | author1 = Flemming AJ | author2 = Shen Z | author3 = Cunha A | author4 = Emmons SW |author5 = Leroi AM | pmid = 10805788 | pmc = 25820 | bibcode = 2000PNAS...97.5285F | doi-access = free }}</ref>
|-
|[[nematode]]
|[[Gastrointestinal tract|intestine]]
|unknown
|<ref>{{Cite journal|last1=Hedgecock|first1=E. M.|last2=White|first2=J. G.|date=January 1985|title=Polyploid tissues in the nematode Caenorhabditis elegans|journal=Developmental Biology|volume=107|issue=1|pages=128–133|issn=0012-1606|pmid=2578115|doi=10.1016/0012-1606(85)90381-1}}</ref>
|}

== Endoreduplication, endomitosis and polytenization ==
Endoreduplication, endomitosis and polytenization are three different processes resulting in polyploidization of a cell in a regulated manner. In endoreduplication cells skip [[Mitosis|M phase]] completely by exiting the mitotic cell cycle in the G<sub>2</sub> phase after completing the S phase several times, resulting in a mononucleated [[polyploid]] cell. The cell ends up with twice as many copies of each chromosome per repeat of the S phase.<ref name=":2">{{Cite journal |last1=Zielke |first1=N. |last2=Edgar |first2=B. A. |last3=DePamphilis |first3=M. L. |date=2013-01-01 |title=Endoreplication |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=5 |issue=1 |article-number=a012948 |doi=10.1101/cshperspect.a012948 |issn=1943-0264 |pmc=3579398 |pmid=23284048}}</ref> Endomitosis is a type of cell cycle variation where mitosis is initiated, but stopped during anaphase and thus cytokinesis is not completed. The cell ends up with multiple nuclei in contrast to a cell undergoing endoreduplication.<ref name=":2" /><ref>{{Cite journal |last1=Shu |first1=Zhiqiang |last2=Row |first2=Sarayu |last3=Deng |first3=Wu-Min |date=June 2018 |title=Endoreplication: The Good, the Bad, and the Ugly |journal=Trends in Cell Biology |volume=28 |issue=6 |pages=465–474 |doi=10.1016/j.tcb.2018.02.006 |issn=0962-8924 |pmc=5962415 |pmid=29567370}}</ref> Therefore depending on how far the cell progresses through mitosis, this will give rise to a mononucleated or [[binucleated cells|binucleated]] polyploid cell. Polytenization arises with under- or overamplification of some genomic regions, creating [[polytene chromosome]]s.<ref name=":0" /><ref name=":1" />

[[File:Endocycling vs. endomitosis.png|thumb|upright=2.5|Endocycling vs. endomitosis]]

==Biological significance==
Based on the wide array of cell types in which endoreduplication occurs, a variety of hypotheses have been generated to explain the functional importance of this phenomenon.<ref name=Edgarone/><ref name=Leeone/> Unfortunately, experimental evidence to support these conclusions is somewhat limited.

===Cell differentiation===
In developing plant tissues the transition from mitosis to endoreduplication often coincides with cell differentiation and [[morphogenesis]].<ref name="Inzeone" /> However it remains to be determined whether endoreduplication and [[polyploidy]] contribute to cell differentiation or vice versa. Targeted inhibition of endoreduplication in [[trichome]] progenitors results in the production of multicellular trichomes that exhibit relatively normal morphology, but ultimately dedifferentiate and undergo absorption into the [[leaf epidermis]].<ref name="Bamsiepeone">{{cite journal |author1=Bramsiepe J |author2=Wester K |author3=Weinl C |author4=Roodbarkelari F |author5=Kasili R |author6=Larkin JC |author7=Hulskamp M |author8=Schnittger A |year=2010 |editor1-last=Qu |editor1-first=Li-Jia |title=Endoreplication Controls Cell Fate Maintenance |journal=PLOS Genetics |volume=6 |issue=6 |article-number=e1000996 |doi=10.1371/journal.pgen.1000996 |pmc=2891705 |pmid=20585618 |doi-access=free}}</ref> This result suggests that endoreduplication and polyploidy may be required for the maintenance of cell identity.

===Cell/organism size===
Cell [[ploidy]] often correlates with cell size,<ref name=Melaragnoone/><ref name=Flemmingone/> and in some instances, disruption of endoreduplication results in diminished cell and tissue size <ref name=Lozanoone>{{cite journal | doi = 10.1016/j.cub.2006.01.048 | title = Regulation of growth by ploidy in Caenorhabditis elegans | journal = Current Biology | volume = 16 | issue = 5 | pages = 493–8 | year = 2006 | author1 = Lozano E | author2 = Saez AG | author3 = Flemming AJ | author4 = Cunha A |author5 = Leroi AM | pmid = 16527744 | doi-access = free | bibcode = 2006CBio...16..493L }}</ref> suggesting that endoreduplication may serve as a mechanism for tissue growth. Relative to mitosis, endoreduplication 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.<ref name=Kondorosione>{{cite journal | doi = 10.1016/S1369-5266(00)00118-7 | title = Plant cell-size control: Growing by ploidy? | journal = Current Opinion in Plant Biology | volume = 3 | issue = 6 | pages = 488–492 | year = 2000 | author1 = Kondorosi E | author2 = Roudier F | author3 = Gendreau E | pmid = 11074380 | bibcode = 2000COPB....3..488K }}</ref> While evidence establishing a connection between ploidy and tissue size is prevalent in the literature, contrary examples also exist.<ref name=Inzeone>{{cite journal | doi = 10.1146/annurev.genet.40.110405.090431 | title = Cell cycle regulation in plant development | journal = Annual Review of Genetics | volume = 40 | pages = 77–105 | year = 2006 | author1 = Inze D | author2 = De Veylder L | pmid = 17094738 }}</ref>

===Oogenesis and embryonic development===
Endoreduplication is commonly observed in [[cell (biology)|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.<ref name=Edgarone/> Consistent with this notion, mutation of the [[Myc]] [[oncogene]] in ''[[Drosophila]]'' [[follicle cells]] results in reduced endoreduplication and abortive [[oogenesis]].<ref name=Mainesone>{{cite journal | doi = 10.1242/dev.00932 | title = ''Drosophila'' dMyc is required for ovary cell growth and endoreplication | journal = Development | volume = 131 | issue = 4 | pages = 775–786 | year = 2004 | author1 = Maines JZ | author2 = Stevens LM | author3 = Tong X |author4 = Stein D | pmid = 14724122 | doi-access = free }}</ref> However, reduction of endoreduplication 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.<ref name=Leiva-Netoone>{{cite journal | doi = 10.1105/tpc.022178 | title = A Dominant Negative Mutant of Cyclin-Dependent Kinase A Reduces Endoreduplication but Not Cell Size or Gene Expression in Maize Endosperm | journal = The Plant Cell | volume = 16 | issue = 7 | pages = 1854–69 | year = 2004 | author1 = Leiva-Neto JT | author2 = Grafi G | author3 = Sabelli PA |author4 = Dante RA |author5 = Woo YM |author6 = Maddock S |author7 = Gordon-Kamm WJ |author8 = Larkins BA | pmid = 15208390 | pmc = 514166 | bibcode = 2004PlanC..16.1854L }}</ref>

===Buffering the genome===
Another hypothesis is that endoreduplication buffers against [[DNA damage]] and [[mutation]] because it provides extra copies of important [[genes]].<ref name=Edgarone/> 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.<ref name=Mortimerone>{{cite journal | doi = 10.2307/3570795 | title = Radiobiological and genetic studies on a polyploid series (haploid to hexaploid) of ''Saccharomyces cerevisiae'' | jstor = 3570795 | journal = Radiation Research | volume = 9 | issue = 3 | pages = 312–326 | year = 1958 | author1 = Mortimer RK | pmid = 13579200 | bibcode = 1958RadR....9..312M | s2cid = 37053611 | url = http://www.escholarship.org/uc/item/9gr1j6n2 | url-access = subscription }}</ref>

===Stress response===
Research in plants suggests that endoreduplication 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.<ref name=Cooksonone>{{cite journal | doi = 10.1111/j.1365-3040.2006.01506.x | title = Cell and leaf size plasticity in ''Arabidopsis'': what is the role of endoreplication? | journal = Plant, Cell and Environment | volume = 29 | pages = 1273–83 | year = 2006 | author1 = Cookson SJ | author2 = Radziejwoski A | author3 = Granier C | issue = 7 | pmid = 17080949 | doi-access = free | bibcode = 2006PCEnv..29.1273C }}</ref> 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-endoreduplication transition occurs in ''[[Drosophila]]'' follicle cells and is activated by [[Notch signaling]].<ref name=Dengone>{{cite journal | title = Notch-Delta signaling induces a transition from mitotic cell cycle to endocycle in ''Drosophila'' follicle cells | journal = Development | volume = 128 | issue = 23 | pages = 4737–46 | year = 2001 | author1 = Deng WM | author2 = Althauser C | author3 = Ruohala-Baker H | doi = 10.1242/dev.128.23.4737 | pmid = 11731454 }}</ref> Entry into endoreduplication involves modulation of [[mitotic]] and [[S-phase]] [[cyclin-dependent kinase]] (CDK) activity.<ref name=Shcherbataone>{{cite journal | doi = 10.1242/dev.01172 | title = The mitotic-to-endocycle switch in''Drosophila'' follicle cells is executed by Notch-dependent regulation of G1/S, G2/M and M/G1 cell-cycle transitions | journal = Development | volume = 131 | issue = 13 | pages = 3169–81 | year = 2004 | author1 = Shcherbata HR | author2 = Althauser C | author3 = Findley SD | author4 = Ruohola-Baker H | pmid = 15175253 | doi-access = free }}</ref> Inhibition of [[M-phase]] CDK activity is accomplished via transcriptional activation of [[Cdh]]/[[fzr]] and repression of the G2-M regulator string/[[cdc25]].<ref name=Shcherbataone/><ref name=Schaefferone>{{cite journal | doi = 10.1016/j.cub.2004.03.040 | title = Notch-dependent Fizzy-related/Hec1/Cdh1 expression is required for the mitotic-to-endocycle transition in ''Drosophila'' follicle cells | journal = Current Biology | volume = 14 | issue = 7 | pages = 630–6 | year = 2004 | author1 = Schaeffer V | author2 = Althauser C | author3 = Shcherbata HR | author4 = Deng WM | author5 = Ruohola-Baker H | pmid = 15062106 | bibcode = 2004CBio...14..630S | hdl = 11858/00-001M-0000-002D-1B8D-3 | s2cid = 18877076 | hdl-access = free }}</ref> 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 phase|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.<ref name=Kaushanskyone>{{cite journal | doi = 10.1172/JCI26674 | title = The molecular mechanisms that control thrombopoiesis | journal = The Journal of Clinical Investigation | volume = 115 | issue = 12 | pages = 3339–47 | year = 2005 | author1 = Kaushansky K | pmid = 16322778 | pmc = 1297257 }}</ref> As with Drosophila follicle cells, endoreduplication in megakaryocytes results from activation of [[S-phase]] cyclin-CDK complexes and inhibition of mitotic cyclin-CDK activity.<ref name=Garciaone>{{cite journal | title = Endoreplication in megakaryoblastic cell lines is accompanied by sustained expression of G1/S cyclins and downregulation of cdc25c| journal = Oncogene | volume = 13 | issue = 4 | pages = 695–703 | year = 1996 | author1 = Garcia P | author2 = Cales C | pmid = 8761290 }}</ref><ref name="Zhangone">{{cite journal |last1=Zhang |first1=Y |last2=Wang |first2=Z |last3=Ravid |first3=K |author-link3=Katya Ravid |year=1996 |title=The cell cycle in polyploid megakaryocytes is associated with reduced activity of cyclin B1-dependent cdc2 kinase |journal=Journal of Biological Chemistry |volume=271 |issue=8 |pages=4266–72 |doi=10.1074/jbc.271.8.4266 |pmid=8626773 |doi-access=free}}</ref>

[[File:Notch regulation of endocycling.png|thumb|upright=1.5|Notch regulation of endocycling]]

Entry into [[S-phase]] during endoreduplication (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 endoreduplication 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,<ref name=Suone>{{cite journal | doi = 10.1083/jcb.140.3.451 | title = Chromosome Association of Minichromosome Maintenance Proteins in Drosophila Endoreplication Cycles | journal = Journal of Cell Biology | volume = 140 | issue = 3 | pages = 451–460 | year = 1998 | author1 = Su TT | author2 = O'Farrell PH | pmid = 9456309 | pmc = 2140170 }}</ref> but it also inhibits pre-RC formation,<ref name=Ariasone>{{cite journal | doi = 10.1101/gad.1508907 | title = Strength in numbers: Preventing rereplication via multiple mechanisms in eukaryotic cells | journal = Genes & Development | volume = 21 | issue = 5 | pages = 497–518 | year = 2004 | author1 = Arias EE | author2 = Walter JC | pmid = 17344412 | doi-access = free }}</ref> 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.<ref name=Leeone/> The mechanism by which cyclin E-Cdk2 inhibits pre-RC formation involves downregulation of [[Anaphase-promoting complex|APC]]-[[Cdh1]]-mediated proteolysis and accumulation of the protein [[Geminin]], which is responsible for sequestration of the pre-RC component [[Cdt1]].<ref name=Narbonne-Reveauone>{{cite journal | doi = 10.1242/dev.016295 | title = APC/CFzr/Cdh1 promotes cell cycle progression during the ''Drosophila'' endocycle | journal = Development | volume = 135 | issue = 8 | pages = 1451–61 | year = 2008 | author1 = Narbonne-Reveau K | author2 = Senger S | author3 = Pal M |author4 = Herr A |author5 = Richardson HE |author6 = Asano M |author7 = Deak P |author8 = Lilly MA | pmid = 18321983 | doi-access = free }}</ref><ref name=Zielkeone>{{cite journal | doi = 10.1101/gad.469108 | title = The anaphase-promoting complex/cyclosome (APC/C) is required for rereplication control in endoreplication cycles | journal = Genes & Development | volume = 22 | issue = 12 | pages = 1690–1703 | year = 2008 | author1 = Zielke N | author2 = Querings S | author3 = Rottig C |author4 = Lehner C |author5 = Sprenger F | pmid = 18559483 | pmc = 2428065 }}</ref>

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 endoreduplication.<ref name=Duronioone>{{cite journal | doi = 10.1101/gad.9.12.1456 | title = Developmental control of the G1 to S transition in ''Drosophila'': Cyclin E is a limiting downstream target of E2F | journal = Genes & Development | volume = 9 | issue = 12 | pages = 1456–68 | year = 1995 | author1 = Duronio RJ | author2 = O'Farrell PH | pmid = 7601350 | doi-access = free }}</ref><ref name=Duroniotwo>{{cite journal | doi =10.1101/gad.9.12.1445 | title =The transcription factor E2F is required for S phase during ''Drosophila'' embryogenesis | journal = Genes & Development | volume = 9 | issue =12 | pages = 1445–55 | year = 1995 | author1 = Duronio RJ | author2 = O'Farrell PH | author3 = Xie JE | author4 = Brook A | author5 = Dyson N | pmid =7601349 | doi-access = free }}</ref><ref name=Duroniothree>{{cite journal | title = Mutations of the Drosophila dDP, dE2F, and cyclin E Genes Reveal Distinct Roles for the E2F-DP Transcription Factor and Cyclin E during the G1-S Transition | journal = Molecular and Cellular Biology | volume = 18 | issue = 1 | pages = 141–151 | year = 1998 | author1 = Duronio RJ | author2 = Bonnette PC | author3 = O'Farrell PH | pmid = 9418862 | pmc = 121467 | doi = 10.1128/MCB.18.1.141 }}</ref> 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.<ref name=Shibutanione>{{cite journal | doi = 10.1016/j.devcel.2008.10.003 | title = Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S phase | journal = Developmental Cell | volume = 15 | issue = 6 | pages = 890–900 | year = 2008 | author1 = Shibutani ST | author2 = de la Cruz AF | author3 = Tran V | author4 = Turbyfill WJ | author5 = Reis T | author6 = Edgar BA | author7 = Duronio RJ | pmid = 19081076 | pmc = 2644461 }}</ref> Post-transcriptional regulation of cyclin E-Cdk2 activity involves [[Ago/Fbw7]]-mediated proteolytic degradation of cyclin E <ref name=Koeppone>{{cite journal | doi = 10.1126/science.1065203 | title = Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase | journal = Science | volume = 294 | issue = 5540 | pages = 173–7 | year = 2001 | author1 = Koepp DM | author2 = Schaefer LK | author3 = Ye X | author4 = Keyomarsi K | author5 = Chu C | author6 = Harper JW |author7 = Elledge SJ | pmid = 11533444 | bibcode = 2001Sci...294..173K | s2cid = 23404627 | doi-access = free }}</ref><ref name=Mobergone>{{cite journal | doi = 10.1038/35095068 | title = Archipelago regulates cyclin E levels in ''Drosophila'' and is mutated in human cancer lines | journal = Nature | volume = 413 | issue = 6853 | pages = 311–6 | year = 2001 | author1 = Moberg KH | author2 = Bell DW | author3 = Wahrer DC | author4 = Haber DA | author5 = Hariharan IK | pmid = 11565033 | s2cid = 4372821 }}</ref> and direct inhibition by factors such as Dacapo and [[p57 (gene)|p57]].<ref name=deNooijone>{{cite journal | doi = 10.1016/S0925-4773(00)00435-4 | title = Expression of cyclin-dependent kinase inhibitor Dacapo is regulated by cyclin E | journal = Mechanisms of Development | volume = 97 | issue = 1–2 | pages = 73–83 | year = 2001 | author1 = de Nooij JC | author2 = Graber KH | author3 = Hariharan IK | pmid = 11025208 | doi-access = free }}</ref><ref name=Ullahone>{{cite journal | doi = 10.1101/gad.1718108 | title = Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity | journal = Genes & Development | volume = 22 | issue = 21 | pages = 3024–36 | year = 2008 | author1 = Ullah Z | author2 = Kohn MJ | author3 = Yagi R | author4 = Vassilev LT | author5 = DePamphilis ML | pmid = 18981479 | pmc = 2577795 }}</ref>

==Premeiotic endomitosis in unisexual vertebrates==

The unisexual salamanders (genus ''[[Ambystoma]]'') are the oldest known unisexual vertebrate lineage, having arisen about 5 million years ago.<ref name="pmid20682056">{{cite journal |vauthors=Bi K, Bogart JP |title=Time and time again: unisexual salamanders (genus Ambystoma) are the oldest unisexual vertebrates |journal=BMC Evol. Biol. |volume=10 |page=238 |year=2010 |issue=1 |pmid=20682056 |pmc=3020632 |doi=10.1186/1471-2148-10-238 |doi-access=free |bibcode=2010BMCEE..10..238B }}</ref> In these polyploid unisexual females, an extra premeiotic endomitotic replication of the genome, doubles the number of chromosomes.<ref name="pmid20358399">{{cite journal |vauthors=Bi K, Bogart JP |title=Probing the meiotic mechanism of intergenomic exchanges by genomic in situ hybridization on lampbrush chromosomes of unisexual Ambystoma (Amphibia: Caudata) |journal=Chromosome Res. |volume=18 |issue=3 |pages=371–82 |year=2010 |pmid=20358399 |doi=10.1007/s10577-010-9121-3 |s2cid=2015354 }}</ref> 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.<ref name="pmid20358399" />

==References==
{{reflist|colwidth=30em}}

[[Category:Genetics]]
[[Category:Cell biology]]
[[Category:Cell cycle]]

Endoreduplication - История изменений

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