Dampened activity of E2F1–DP and Myb–MuvB transcription factors in<i>Drosophila</i>endocycling cells

Maqbool, Shahina; Mehrotra, Sonam; Kolpakas, Alexis; Durden, Chris; Zhang, Bingqing; Zhong, Hua Ning; Calvi, Brian R.

doi:10.1242/jcs.064519

Cited by 48 publications

(67 citation statements)

References 107 publications

(134 reference statements)

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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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Section: Discussionmentioning

confidence: 99%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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“…Endocycle entry in these tissues is promoted by transcriptional repression of genes that are required for mitosis, for example mitotic cyclins Cyclin A (CycA) and Cyclin B (CycB), and increased expression of fzr/Cdh1 (rap -FlyBase), which encodes a subunit of the anaphase-promoting complex (APC) ubiquitin ligase (Maqbool et al, 2010;Narbonne Reveau et al, 2008;Schaeffer et al, 2004;Sigrist and Lehner, 1997;Zielke et al, 2008). APC Cdh1 ubiquitinates CycB and other proteins required for mitosis, targeting them for destruction by the proteasome (Manchado et al, 2010;Pesin and Orr-Weaver, 2008;Wäsch et al, 2010).…”

Section: Research Articlementioning

confidence: 99%

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

et al. 2014

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The endocycle is a common developmental cell cycle variation wherein cells become polyploid through repeated genome duplication without mitosis. We previously showed that Drosophila endocycling cells repress the apoptotic cell death response to genotoxic stress. Here, we investigate whether it is differentiation or endocycle remodeling that promotes apoptotic repression. We find that when nurse and follicle cells switch into endocycles during oogenesis they repress the apoptotic response to DNA damage caused by ionizing radiation, and that this repression has been conserved in the genus Drosophila over 40 million years of evolution. Follicle cells defective for Notch signaling failed to switch into endocycles or differentiate and remained apoptotic competent. However, genetic ablation of mitosis by knockdown of Cyclin A or overexpression of fzr/Cdh1 induced follicle cell endocycles and repressed apoptosis independently of Notch signaling and differentiation. Cells recovering from these induced endocycles regained apoptotic competence, showing that repression is reversible. Recovery from fzr/Cdh1 overexpression also resulted in an error-prone mitosis with amplified centrosomes and high levels of chromosome loss and fragmentation. Our results reveal an unanticipated link between endocycles and the repression of apoptosis, with broader implications for how endocycles may contribute to genome instability and oncogenesis.

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“…The differences in expression of replication genes support the model (42,43) that limiting expression of proteins needed for initiation of DNA replication leads to a slower S phase and prevents the duplication of genome regions that are late replicating. This provides an advantage of not replicating gene-poor regions such as heterochromatin, but at the cost of slow endocycles.…”

Section: Discussionmentioning

confidence: 62%

“…reduction in the expression of genes involved in DNA replication (10,42). It has been proposed that reduced expression of genes required for DNA replication leads to a slowed S phase and failure to replicate genomic regions normally replicated late in S phase (43), possibly leading to underreplication in these tissues.…”

Section: Tgcs Mksmentioning

confidence: 99%

Fundamental differences in endoreplication in mammals and Drosophila revealed by analysis of endocycling and endomitotic cells

Sher

Stetina

Bell

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Throughout the plant and animal kingdoms specific cell types become polyploid, increasing their DNA content to attain a large cell size. In mammals, megakaryocytes (MKs) become polyploid before fragmenting into platelets. The mammalian trophoblast giant cells (TGCs) exploit their size to form a barrier between the maternal and embryonic tissues. The mechanism of polyploidization has been investigated extensively in Drosophila , in which a modified cell cycle—the endocycle, consisting solely of alternating S and gap phases—produces polyploid tissues. During S phase in the Drosophila endocycle, heterochromatin and specific euchromatic regions are underreplicated and reduced in copy number. Here we investigate the properties of polyploidization in murine MKs and TGCs. We induced differentiation of primary MKs and directly microdissected TGCs from embryonic day 9.5 implantation sites. The copy number across the genome was analyzed by array-based comparative genome hybridization. In striking contrast to Drosophila , the genome was uniformly and integrally duplicated in both MKs and TGCs. This was true even for heterochromatic regions analyzed by quantitative PCR. Underreplication of specific regions in polyploid cells is proposed to be due to a slower S phase, resulting from low expression of S-phase genes, causing failure to duplicate late replicating genomic intervals. We defined the transcriptome of TGCs and found robust expression of S-phase genes. Similarly, S-phase gene expression is not repressed in MKs, providing an explanation for the distinct endoreplication parameters compared with Drosophila . Consistent with TGCs endocycling rather than undergoing endomitosis, they have low expression of M-phase genes.

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Dampened activity of E2F1–DP and Myb–MuvB transcription factors inDrosophilaendocycling cells

Cited by 48 publications

References 107 publications

The function of Drosophila p53 isoforms in apoptosis

The function of Drosophila p53 isoforms in apoptosis

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

Fundamental differences in endoreplication in mammals and Drosophila revealed by analysis of endocycling and endomitotic cells

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