Endoreplication and polyploidy: insights into development and disease

Abstract

Polyploid cells have genomes that contain multiples of the typical diploid chromosome number and are found in many different organisms. Studies in a variety of animal and plant developmental systems have revealed evolutionarily conserved mechanisms that control the generation of polyploidy and have recently begun to provide clues to its physiological function. These studies demonstrate that cellular polyploidy plays important roles during normal development and also contributes to human disease, particularly cancer.

Fig. 1.

Endoreplication results from cell cycle plasticity during development. (A) A canonical cell division cycle consists of four distinct phases. Chromosomes are duplicated during S phase and segregated to daughter cells during M phase. (B) Endoreplication can occur either by endomitosis, a cell cycle that displays features of mitosis but lacks cytokinesis, or by endocycling in which periods of S and G phase alternate with no cell division.

Fig. 2.

The endoreplication oscillator in Drosophila salivary glands. The core regulatory relationships between E2f1, Cyclin E and CRL4^Cdt2 (top) give rise to out-of-phase oscillations in the activity of key regulatory proteins controlling S phase (bottom). E2f1, APC^Fzr/Cdh1 and Cdt1 (red) are active during G phase, whereas the Cyclin E/Cdk2 complex, CRL4^Cdt2 and Geminin (black) are active during S phase. Note that CRL4^Cdt2 activity is dependent on DNA replication, which is triggered by the Cyclin E/Cdk2 complex, and that Cdt1 is inhibited both by Geminin binding and CRL4^Cdt2-mediated destruction.

Fig. 3.

Signals triggering polyploidy. (A-C) Signals that regulate the mitosis-to-endoreplication switch in mammals (A; trophoblast giant cells, TGCs), plant seedlings (B; hypocotyl) and insects (C; Drosophila ovarian follicle cells).

Fig. 4.

The reciprocal relationship between endoreplication and genome stability. Endoreplication can promote genome instability in the form of amplified centrosomes and an increased tolerance for DNA damage. Conversely, DNA damage, chromatin changes and telomere defects are all examples of genome instability forms that have been demonstrated to initiate endoreplication.

Fig. 5.

Potential molecular mechanisms of polyploid tumor formation. Distinct molecular alterations can influence each step of the progression from diploid to polyploid to tumorous proliferation. Shown here are recently identified mechanisms implicated in this progression. Genetic factors such as Rb loss or KLHDC88 mutation can promote endoreplication. Once cells achieve polyploidy, p53 can mediate cell cycle arrest or cell death. Conversely, in the absence of p53 or its target p21, or following administration of toxins such as diethylnitrosamine or aflatoxin B1 (see Reed et al., 2009 and McClendon et al., 2011), or in the presence of increased Myc (see Saddic et al., 2011), tumorigenesis may result.