Loss of polarity correlates with progression of epithelial cancers, but how plasma membrane misorganization drives oncogenic transcriptional events remains unclear. The polarity regulators of the Drosophila Scribble (Scrib) module are potent tumor suppressors and provide a model for mechanistic investigation. RNA profiling of Scrib mutant tumors reveals multiple signatures of neoplasia, including altered metabolism and dedifferentiation. Prominent among these is upregulation of cytokine-like Unpaired (Upd) ligands, which drive tumor overgrowth. We identified a polarity-responsive enhancer in upd3, which is activated in a coincident manner by both JNK-dependent Fos and aPKC-mediated Yki transcription. This enhancer, and Scrib mutant overgrowth in general, are also sensitive to activity of the Polycomb Group (PcG), suggesting that PcG attenuation upon polarity loss potentiates select targets for activation by JNK and Yki. Our results link epithelial organization to signaling and epigenetic regulators that control tissue repair programs, and provide insight into why epithelial polarity is tumor-suppressive.DOI: http://dx.doi.org/10.7554/eLife.03189.001

A prevailing paradigm posits that Polycomb Group (PcG) proteins maintain stem cell identity by repressing differentiation genes, and abundant evidence points to an oncogenic role for PcG in human cancer 1,2. Here we demonstrate using Drosophila that a conventional PcG complex can also have a potent tumor suppressive activity. Mutations in all core PRC1 components cause dramatic hyperproliferation of eye imaginal tissue, accompanied by deregulation of epithelial architecture. The mitogenic JAK/STAT pathway is strongly and specifically activated in mutant tissue; activation is driven by transcriptional upregulation of Unpaired (Upd) family ligands. We show that upd genes are direct targets of PcG-mediated repression in imaginal discs. Ectopic JAK/STAT activity is sufficient to induce overproliferation, while reduction of JAK/STAT activity suppresses the PRC1 mutant tumor phenotype. These findings show that PcG proteins can restrict growth directly by silencing mitogenic signaling pathways, shedding light onto an epigenetic mechanism underlying tumor suppression.

The replication factors Cdt1 and Cdc6 are essential for origin licensing, a prerequisite for DNA replication initiation. Mechanisms to ensure that metazoan origins initiate once per cell cycle include degradation of Cdt1 during S phase and inhibition of Cdt1 by the geminin protein. Geminin depletion or overexpression of Cdt1 or Cdc6 in human cells causes rereplication, a form of endogenous DNA damage. Rereplication induced by these manipulations is however uneven and incomplete, suggesting that one or more mechanisms restrain rereplication once it begins. We find that both Cdt1 and Cdc6 are degraded in geminin-depleted cells. We further show that Cdt1 degradation in cells that have rereplicated requires the PCNA binding site of Cdt1 and the Cul4 DDB1 ubiquitin ligase, and Cdt1 can induce its own degradation when overproduced. Cdc6 degradation in geminin-depleted cells requires Huwe1, the ubiquitin ligase that regulates Cdc6 after DNA damage. Moreover, perturbations that specifically disrupt Cdt1 and Cdc6 degradation in response to DNA damage exacerbate rereplication when combined with geminin depletion, and this enhanced rereplication occurs in both human cells and in Drosophila melanogaster cells. We conclude that rereplication-associated DNA damage triggers Cdt1 and Cdc6 ubiquitination and destruction, and propose that this pathway represents an evolutionarily conserved mechanism that minimizes the extent of rereplication.One of the critical events in the cell division cycle is complete and precise duplication of the genome. In eukaryotic cells, origins of DNA replication acquire replication competence through the assembly of a prereplication complex (preRC) 3 in the G 1 phase of the cell cycle. PreRCs are assembled by the sequential origin binding of the origin recognition complex (ORC), Cdc6, Cdt1, and the minichromosome maintenance complex (MCM). Origins harboring preRCs are licensed for replication but do not initiate DNA synthesis until S phase begins and the Cdc7 and Cdk2 kinases are activated (1-3). The large genomes of metazoan cells necessitate the utilization of thousands of origins, but each origin that initiates DNA synthesis must do so only once. Failure to maintain this control has been linked to genome instability and oncogenesis (4, 5), but the cellular consequences of rereplication are not fully understood. Multiple regulatory mechanisms operate to ensure that any origins that have "fired" do not fire again by blocking preRC assembly after the G 1 to S phase transition. Among the most important of these mechanisms are degradation of Cdt1 during S phase and inhibition of Cdt1 by the geminin protein. Geminin depletion, overexpression of Cdt1, or overexpression of Cdc6 causes rereplication, which ultimately triggers a DNA damage response (6 -11) and can promote tumorigenesis (4, 5). Rereplication induced by these manipulations is however incomplete, with the extent of rereplication varying widely among different cell lines. These observations suggest that in addition to the mechanisms that bloc...

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