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Endocycles: a recurrent evolutionary innovation for post-mitotic cell growth

Nature Reviews Molecular Cell Biology volume 15, pages 197–210 (2014)Cite this article

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A Corrigendum to this article was published on 11 March 2014

This article has been updated

Key Points

  • Endoreplication occurs in multiple cell types in most animals and plants, typically in terminally differentiated cells. The final level of ploidy is highly cell type- and species-specific.

  • Due to their increased genomic DNA content, endocycling cells can achieve large sizes or massive output of secreted protein products.

  • Endocycle onset requires suppression of mitosis. This is achieved by different mechanisms in different species and cell types. These include transcriptional repression of mitotic cyclin expression, APC/C (anaphase promoting complex, also known as the cyclosome) -mediated degradation of mitotic cyclins and inhibition of cyclin-dependent kinase (CDK) activity. This inhibition often relies on CDK inhibitory proteins.

  • Endoreplication onset and progression are also broadly affected by the activities of the E2F transcription factors and their co-repressors, the RB proteins, which affect the expression of genes involved in mitosis and DNA replication.

  • Endocycle progression involves many of the same factors that control G1–S phase transitions and G1 length in mitotically proliferating cells. Key requirements are the suppression of mitotic CDK (M-CDK) activity, and the retention of oscillating S phase CDK (S-CDK) activity.

  • Various upstream inputs control the speed of endocycling and the timing of endocycle exit. Together these two factors determine final ploidy and also affect cell size. Upstream inputs include nutrients and growth factors, target of rapamycin (TOR) signalling and (in plants) light exposure.

  • Cross-species and cross-kingdom comparisons suggest that endocycles are an ancient cellular innovation that probably evolved many times.

Abstract

In endoreplication cell cycles, known as endocycles, cells successively replicate their genomes without segregating chromosomes during mitosis and thereby become polyploid. Such cycles, for which there are many variants, are widespread in protozoa, plants and animals. Endocycling cells can achieve ploidies of >200,000 C (chromatin-value); this increase in genomic DNA content allows a higher genomic output, which can facilitate the construction of very large cells or enhance macromolecular secretion. These cells execute normal S phases, using a G1–S regulatory apparatus similar to the one used by mitotic cells, but their capability to segregate chromosomes has been suppressed, typically by downregulation of mitotic cyclin-dependent kinase activity. Endocycles probably evolved many times, and the various endocycle mechanisms found in nature highlight the versatility of the cell cycle control machinery.

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Figure 1: Endocycle variants.
Figure 2: The CDK threshold model.
Figure 3: Transitioning from mitotic cycles to endocycles.
Figure 4: Models for endocycle progression.

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Change history

  • 11 March 2014

    In the above article, reference 168 (page 210) was incorrectly cited. The citation appeared as: Tamori, Y. & Deng, W. M. Cell competition and its implications for development and cancer. J. Genet. Genom. 38, 483–495 (2011). The correct citation is: Tamori, Y. & Deng, W. M. Tissue repair through cell competition and compensatory cellular hypertrophy in postmitotic epithelia. Dev. Cell 25, 350–363 (2013). This has now been corrected in the online version of the article.

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Acknowledgements

B.A.E. was supported by European Research Council Advanced Grant 268515 and the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), N.Z. by the DKFZ, and C.G. by MINECO (BFU2009-9783 and BFU2012-34821) and by an institutional grant from Fundacion Ramon Areces. The authors thank C. de Renty, Z. Ullah and M. Depamphilis for the image of TGCs shown in figure 4Bc and B. Desvoyes and S. Otero for the image of Arabidopsis thaliana shown in figure 4Cc.

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Authors and Affiliations

  1. German Cancer Research Center-Center for Molecular Biology Heidelberg Alliance, Im Neuenheimer Feld 282, Heidelberg, 69120, Germany

    Bruce A. Edgar & Norman Zielke

  2. Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Nicolas Cabrera 1, Cantoblanco, Madrid, 28049, Spain

    Crisanto Gutierrez

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  1. Bruce A. Edgar
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Supplementary information

Supplementary information S1 (box)

Endocycle-to-mitosis transitions and ploidy reversal (PDF 609 kb)

Supplementary information S2 (table)

Endocycle phenotypes in Drosophila melanogaster (PDF 630 kb)

Supplementary information S3 (table)

Endocycle phenotypes in mammals (PDF 617 kb)

Supplementary information S4 (table)

Endocycle phenotypes in Arabidopsis thaliana (PDF 634 kb)

Supplementary information S5 (table)

Upstream regulators of the endocycle (PDF 601 kb)

PowerPoint slides

Glossary

Polyploid

Refers to the genomic DNA of a cell in which entire chromosomes have been re-replicated. 'Polytene' refers to a subset of polyploid cells in which homologous chromosome arms are closely paired, which leads to the appearance of single, giant chromosomes.

Endomitosis

A cell cycle that includes S phase and many mitotic processes, including chromosome condensation, nuclear envelope breakdown and spindle formation. Endomitotic cell cycles abort mitosis during metaphase or anaphase, and lack cytokinesis. However, kinetochores and centromeres might or might not split at the metaphase–anaphase transition; these cycles do not produce two nuclei.

Endopolyploidy

Polyploidy that occurs in somatic cell lineages, following endoreplication of diploid progenitor cells. Not to be confused with germline polyploidy, which is heritable, occurs in all cells in an organism and can affect speciation.

Chromatin-values

(C). C-values indicate DNA content as a multiple of the normal haploid genome. A sperm or egg nucleus is 1 C, a zygote is 2 C and a diploid cell in G2 is 4 C. A cell that has undergone one round of endoreplication (starting from G2) is 8 C, two rounds result in 16 C, and so on.

Trophoblast giant cells

(TGCs). Mammalian placental cells that are essential for embryonic implantation and placentation, in which they function as a barrier between the maternal blood supply and the embryo proper.

Cell expansion

A term referring to the cell size increase in plant cells. As this often occurs by increasing the size of the fluid-filled vacuole, it is not necessarily accompanied by increased mass of proteinaceous cytoplasm.

Pre-replication complexes

(PreRCs). This multi-protein complex assembles on the DNA during G1 phases, at origins of replication, using pre-bound origin replication complex proteins as a template. PreRCs are necessary for the initiation of DNA replication and include CDC10-dependent transcript 1 (CDT1), CDC6 and the replication-associated DNA helicase, which is composed of mini-chromosome maintenance complex 2–7 (MCM2–7).

Hypertrophy

An increase in cell size beyond the norm for a given cell type. This may or may not be associated with endopolyploidy.

Aneuploidy

A cell having an aberrant number of chromosomes that is not a multiple of two of the number of chromosomes found in the normal haploid germline. 'Segmental aneuploidy' refers to changes in gene copy number owing to deletions or duplications of portions of chromosomes.

APC/C

(Anaphase promoting complex, also known as the cyclosome). A conserved complex of >ten proteins that has E3 ubiquitin ligase activity and targets important mitotic regulators for 26S proteasome-dependent degradation beginning at metaphase–anaphase transitions. The APC/C has two regulatory adaptor proteins: CDC20 (also known as FZY), which is active during mitosis, and CDC20 homologue 1 (CDH1; also known as FZR), which is active during G1 and some endocycle gap phases.

CRL4Cdt2

An E3 ubiquitin ligase complex composed of Cullin 4 (Cul4), Ddb1, Cdt2 (Cdc10-dependent transcript 2; a DCAF), and Rbx1. This ubiquitin ligase acts specifically on substrates that are recruited to DNA replication fork complexes by a PIP box (PCNA-interacting protein) motif, which binds the DNA replication fork protein, PCNA (proliferating cell nuclear antigen).

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Edgar, B., Zielke, N. & Gutierrez, C. Endocycles: a recurrent evolutionary innovation for post-mitotic cell growth. Nat Rev Mol Cell Biol 15, 197–210 (2014). https://doi.org/10.1038/nrm3756

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