Developmentally programmed endoreduplication in animals

Abstract

Development of a fertilized egg into an adult human requires trillions of cell divisions, the vast majority of which duplicate their genome once and only once. Nevertheless, trophoblast giant cells and megakaryocytes in mammals circumvent this rule by duplicating their genome multiple times without undergoing cell division, a process generally referred to as 'endoreduplication'. In contrast, arthropods such as Drosophila endoreduplicate their genome in most larval tissues, as well as in many adult tissues. Endoreduplication requires that cells prevent entrance into or completion of mitosis and cytokinesis under conditions that permit assembly of prereplication complexes. In addition, cells must prevent induction of apoptosis in response to incomplete DNA replication or DNA damage that may occur during the ensuing sequence of 'endocycles'. Thus, developmentally regulated endoreduplication results in terminal cell differentiation. Recent progress has revealed both differences and similarities in the mechanisms employed by flies and mammals to change from mitotic cell cycles to 'endocycles'. The critical step, however, appears to be switching from a CDK-dependent form of the anaphase promoting complex (APC) to one that functions only in the absence of CDK activity.

The malarial CDK Pfmrk and its effector PfMAT1 phosphorylate DNA replication proteins and co-localize in the nucleus

“…Interestingly, even during endoreduplication (which occurs during differentiation of mammalian trophoblasts and megakaryoblasts), CDKs are involved in regulating the endocyclic process. In fact, differences in CDK regulation are responsible for maintaining either a "normal" mitotic cell cycle versus an endocycle by controlling the assembly and firing of the pre-RC [53]. Many components of the pre-RC and RC are encoded in the plasmodial genome and several have been characterized including MCMs, ORCs, DNA polymerases and PCNA [31,[54][55][56][57][58].…”

p27Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

“…While the C value increases during S-phase, remaining duplicated during G2, the N value remains unaltered as the cell progresses through the cell cycle. [10][11][12][13] Polyploidy, defined as the presence in the cell nucleus of more than 2 sets of chromosomes, can affect all the cells of the organism. In this case, it is referred to as germinal polyploidy.…”

“…Somatic polyploidy has several advantages for the affected cells including a better response to metabolic and/or genotoxic stress and a lower sensibility to apoptotic stimuli. 10,11,20,21 In mammals and higher vertebrates different cell types have been shown to be polyploid, including trophoblast giant cells, 10,11,,22 hepatocytes, 23,24 megakaryocytes, 25 keratinocytes, 26 and vascular smooth cells. 27 Endoreplication represents a major mechanism leading to developmental programmed somatic polyploidy.…”

“…27 Endoreplication represents a major mechanism leading to developmental programmed somatic polyploidy. [10][11][12] This process consists of successive rounds of DNA synthesis in the absence of mitosis (endocycles), thus leading to cells with a DNA content higher than 2C. Although the mechanism of endoreplication is far from being completely understood, it seems to be dependent on the levels and activity of the Cdk/Cyclin complex after the completion of every S phase, the oscillations of Cyclin E and Geminin levels, and the localization of the minichromosome maintenance protein complexes.…”

“…Although the mechanism of endoreplication is far from being completely understood, it seems to be dependent on the levels and activity of the Cdk/Cyclin complex after the completion of every S phase, the oscillations of Cyclin E and Geminin levels, and the localization of the minichromosome maintenance protein complexes. [10][11][12]28 Endoreplication can be mimicked by inhibition of Cdk1 activity, 11 and the subsequent prevention of the mitotic process. Moreover, cyclin E/Cdk2 is the G1 Cdk complex crucial for DNA synthesis initiation during the endoreplicative process.…”