Induction of endocycles represses apoptosis independently of differentiation and predisposes cells to genome instability

Hassel, Christiane; Zhang, Bingqing; Dixon, Michael J.; Calvi, Brian R.

doi:10.1242/dev.098871

Cited by 82 publications

(113 citation statements)

References 116 publications

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“…We previously proposed that the apoptotic response to genotoxic stress must be tightly repressed in polyploid endocycling cells because they have constitutive genotoxic stress caused by under-replication of heterochromatic DNA [19], [83], [84]. Consistent with a possible linkage between the endocycle program and apoptotic repression, we recently found that experimentally-induced endocycling cells (iECs) repress apoptosis independent of cell differentiation [25]. It is clear that low levels of p53 protein is not the only mechanism of repression because over-expression of p53A resulted in abundant protein in endocycling cells, but failed to induce H99 transcription or apoptosis.…”

Section: Discussionmentioning

confidence: 90%

Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in Drosophila Endocycling Cells

Zhang

Mehrotra

et al. 2014

PLoS Genet

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Apoptotic cell death is an important response to genotoxic stress that prevents oncogenesis. It is known that tissues can differ in their apoptotic response, but molecular mechanisms are little understood. Here, we show that Drosophila polyploid endocycling cells (G/S cycle) repress the apoptotic response to DNA damage through at least two mechanisms. First, the expression of all the Drosophila p53 protein isoforms is strongly repressed at a post-transcriptional step. Second, p53-regulated pro-apoptotic genes are epigenetically silenced in endocycling cells, preventing activation of a paused RNA Pol II by p53-dependent or p53-independent pathways. Over-expression of the p53A isoform did not activate this paused RNA Pol II complex in endocycling cells, but over-expression of the p53B isoform with a longer transactivation domain did, suggesting that dampened p53B protein levels are crucial for apoptotic repression. We also find that the p53A protein isoform is ubiquitinated and degraded by the proteasome in endocycling cells. In mitotic cycling cells, p53A was the only isoform expressed to detectable levels, and its mRNA and protein levels increased after irradiation, but there was no evidence for an increase in protein stability. However, our data suggest that p53A protein stability is regulated in unirradiated cells, which likely ensures that apoptosis does not occur in the absence of stress. Without irradiation, both p53A protein and a paused RNA pol II were pre-bound to the promoters of pro-apoptotic genes, preparing mitotic cycling cells for a rapid apoptotic response to genotoxic stress. Together, our results define molecular mechanisms by which different cells in development modulate their apoptotic response, with broader significance for the survival of normal and cancer polyploid cells in mammals.

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Section: Discussionmentioning

confidence: 90%

Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in Drosophila Endocycling Cells

Zhang

Mehrotra

et al. 2014

PLoS Genet

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“…Western blotting was performed as previously described. 74,75 Antibody dilutions are: mouse anti p53 (C11, Santa Cruz, Dallas, TX, USA) 1 : 500, mouse anti-α-tubulin (clone DM1A, Sigma-Aldrich Corp., St. Louis, MO, USA) 1 : 5000, and anti-mouse secondary antibody, peroxidase labeled (KPL, Gaithersburg, MD, USA) at 1 : 5000.…”

Section: Discussionmentioning

confidence: 99%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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The p53 protein is a major mediator of the cellular response to genotoxic stress and is a crucial suppressor of tumor formation. In a variety of organisms, p53 and its paralogs, p63 and p73, each encode multiple protein isoforms through alternative splicing, promoters, and translation start sites. The function of these isoforms in development and disease are still being defined. Here, we evaluate the apoptotic potential of multiple isoforms of the single p53 gene in the genetic model Drosophila melanogaster. Most previous studies have focused on the p53A isoform, but it has been recently shown that a larger p53B isoform can induce apoptosis when overexpressed. It has remained unclear, however, whether one or both isoforms are required for the apoptotic response to genotoxic stress. We show that p53B is a much more potent inducer of apoptosis than p53A when overexpressed. Overexpression of two newly identified short isoforms perturbed development and inhibited the apoptotic response to ionizing radiation. Analysis of physiological protein expression indicated that p53A is the most abundant isoform, and that both p53A and p53B can form a complex and co-localize to sub-nuclear compartments. In contrast to the overexpression results, new isoformspecific loss-of-function mutants indicated that it is the shorter p53A isoform, not full-length p53B, that is the primary mediator of pro-apoptotic gene transcription and apoptosis after ionizing radiation. Together, our data show that it is the shorter p53A isoform that mediates the apoptotic response to DNA damage, and further suggest that p53B and shorter isoforms have specialized functions.

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“…When exposed to ionizing radiation, polyploid cells accumulate double-stranded DNA breaks, yet repress the DNA damage response checkpoint. 47 In addition, genetically inducing an endocycle is sufficient to make a cell more resistant to apoptosis 47 thereby giving polyploid cells a survival advantage. Polyploidy has also long been correlated with an increased resistance to stress.…”

Section: The Polyploid Advantagementioning

confidence: 99%

Wound-Induced Polyploidy Is Required for Tissue Repair

Losick

2016

Advances in Wound Care

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Induction of endocycles represses apoptosis independently of differentiation and predisposes cells to genome instability

Cited by 82 publications

References 116 publications

Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in Drosophila Endocycling Cells

Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in Drosophila Endocycling Cells

The function of Drosophila p53 isoforms in apoptosis

Wound-Induced Polyploidy Is Required for Tissue Repair

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