Endoreplication and polyploidy: insights into development and disease

Abstract

SummaryPolyploid 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.Key words: Cancer, Endocycle, Endomitosis, Endoreplication, Genome instability IntroductionPolyploid cells, which contain multiples of the diploid genome equivalent, have been studied for many years, nearly as long as chromosomes themselves have been studied. Now, over a century after the discovery of polyploidy, we know much about the molecular mechanisms that generate cellular polyploidy, but comparably little regarding the physiological function of the polyploid state. This discrepancy exists despite the frequent occurrence of polyploid cells in most multicellular organisms, as well as in human cancers. An important aspect of deciphering the roles for polyploidy lies in understanding the regulation of endoreplication, a cell cycle variation that generates a polyploid genome by repeated rounds of DNA replication in the absence of cell division. Recent advances show that, although some differences exist in the diverse endoreplication programs found from protists to humans, core principles can be applied. New work in genetic model organisms has identified cases in which programmed endoreplication plays key roles in development. Furthermore, recent evidence indicates that endoreplication can confer genome instability, a major cancer-enabling property. In this Primer (see Box), we review such recent discoveries, focusing on work carried out in the past 3 years, and refer the reader to other comprehensive reviews on this topic Lee et al., 2009). From these new insights emerge unifying themes regarding endoreplication that hold promise of elucidating the advantages, as well as the potential disadvantages, of polyploidy. Endoreplication and developmentEndoreplication is typically studied in the context of endopolyploidy, which refers to the presence of polyploid cells in an otherwise diploid organism. Diverse levels of polyploidy occur throughout nature (Table 1). Although polyploidy is well appreciated in plants , many different animal tissues, including the skin, gut, placenta, liver, brain and blood have polyploid cells (Table 1) (Laird et al., 1980;Corash et al., 1989;Fox et al., 2010; Hedgecock and White, 1985;Melaragno et al., 1993;Sherman, 1972;Unhavaithaya and Orr-Weaver, 2012;Zanet et al., 2010). Interestingly, endoreplication is not limited to multi-cellular organisms, with examples described in ciliated protozoa (Yin et al., 2010) and even bacteria (Mendell et al., 2008).Two primary forms of endoreplication have been described: endocycling and endomitosis (Fig. 1). Endocycles are compos...

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization

“…Therefore, the duplicated chromosomes produced by endoreplication may be packed into separated nucleus, thus forming multinucleated cells. 1,27,34,42 Our results showed that most of the polyploid decidual cells are manifested as binucleated and arrested in G2/M phase, suggesting that endoreplication and M phase arrest may be the main mechanisms involved in decidual cell polyploidization. CDK1, also known as cell division control protein 2, controls the onset of mitotic phase.…”

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

“…Recent work suggests that pathological polyploidization is an adaptation to genomic stress (60). Cells respond to a diverse array of DNA lesions with an evolutionarily conserved DNA damage response (61).…”

Why do plants need so many cyclin-dependent kinase inhibitors?

“…In some circumstances, CKIs also promote a modified cell cycle known as endoreplication or endoreduplication, in which mitosis and cytokinesis are bypassed, but DNA replication continues, resulting in cells with increased ploidy. 1,2 The number of genome-encoded CKIs varies among different species and kingdoms, and some lineages have more than one distinct type of CKI. For example, mammals have 2 CKI families, CDK interacting protein/kinase inhibitory protein (CIP/KIP) and INHIBITOR of CDK4 (INK4) and these 2 families share no sequence similarity.…”