Clinical treatment responsiveness in recurrent canine lymphoma correlates with Anaphase Promoting Complex activity
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PROVIDER: PRJNA496432 | ENA |
REPOSITORIES: ENA
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Project description:The development of drug resistant cancer is a chronic threat to those undergoing cancer treatment. Why cells develop resistance to drugs has been studied extensively, with many molecular mechanisms driving the process now understood, yet it remains a chronic problem with few treatment options. In this study we treated companion canines presenting to the Western College of Veterinary Medicine in Saskatoon with drug resistant lymphoma with adjunct metformin along with their normal chemotherapy. We obtained repeated tumor samples from 4 canines undergoing this therapy and assessed RNA obtained from these samples by microarray. We identified a highly interconnected 201 gene set upregulated in the 4 dogs that was associated with tumor progression. This gene set was enriched in genes involved in mitotic progression and chromosome maintenance. We observed that mRNAs encoding substrates of the Anaphase Promoting Complex (APC) were integral to this gene set. Treatment with metformin lowered both protein and RNA levels of these substrates, while relapse resulted in elevated levels once again. The change in APC substrates clearly reflects disease progression, indicating that APC activity is critical for cellular homeostasis and loss of this activity can result in tumor progression.
2018-12-01 | GSE121242 | GEO
Project description:Anaphase-promoting complex-dependent control of cell identity
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Project description:Tissue development and homeostasis rely on the proliferation of progenitor cells, whose identities are established by tightly controlled gene expression networks. However, mRNA synthesis is inhibited during mitosis, and the transcriptional programs that define a cell type must be restarted upon entry into each new cell cycle; how this is accomplished is poorly understood. Here, we identified a ubiquitin-dependent mechanism that integrates gene expression with cell division to preserve cell identity. We found that WDR5 and TBP, which bind active promoters during interphase, recruit the E3 ligase anaphase-promoting complex (APC/C) to specific transcription start sites during mitosis. This allows the APC/C to locally decorate histones with K11/K48-linked ubiquitin chains, which destabilizes nucleosomes and ensures continued gene expression in the next cell cycle. Mitotic exit and transcription re-initiation are therefore controlled by the same essential regulator, the APC/C, which provides a robust mechanism to maintain cell identity through cell division.
2020-02-03 | GSE122298 | GEO
Project description:Predictive Biomarkers for the Responsiveness of Recurrent Glioblastomas to Activated Killer Cell Immunotherapy
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Project description:Chromosome segregation requires both the separation of sister chromatids and the sustained condensation of chromatids during anaphase. In yeast cells, cohesin is not only required for sister chromatid cohesion but also plays a major role in determining the structure of individual chromatids in metaphase. Separase cleavage is thought to remove all cohesin complexes from chromosomes to initiate anaphase. It is thus not clear how the length and organisation of segregating chromatids are maintained during anaphase in the absence of cohesin. Here we show that degradation of cohesin at the anaphase onset causes aberrant chromatid segregation. Hi-C analysis on segregating chromatids demonstrates that cohesin depletion causes loss of intrachromatid organisation. Surprisingly, TEV-mediated cleavage of cohesin does not dramatically disrupt chromatid organisation in anaphase, explaining why bulk segregation is achieved. In addition, we identified a small pool of cohesin complexes bound to telophase chromosomes in wildtype cells and show that they play a role in the organisation of centromeric regions. Our data demonstrate that in yeast cells, cohesin function is not over in metaphase, but extends to the anaphase period when chromatids are segregating.
2022-10-01 | GSE183481 | GEO
Project description:Sister chromatid cohesion relies on cohesins, a group of proteins that forms a ring-shaped complex embracing sister chromatids. Cohesion is established during S phase and is removed when cohesin Scc1 is cleaved by the protease separase at anaphase onset. During this process, the cohesin subunit Smc3 undergoes a cycle of acetylation: Smc3 acetylation by Eco1 in S phase stabilizes cohesin association with chromosomes, and its deacetylation by Hos1 in anaphase allows re-use of Smc3 in the next cell cycle. Here we find that Smc3 deacetylation by Hos1 has a more immediate effect in early anaphase of budding yeast. Without Hos1, sister chromatid separation and segregation are significantly delayed. Smc3 deacetylation facilitates removal of cohesins from chromosomes, without changing the Scc1 cleavage efficiency, thus promoting dissolution of cohesion. This action is probably due to disengagement of Smc1–3 heads, prompted by de-repression of their ATPase activity. We suggest Scc1 cleavage per se is insufficient for efficient dissolution of cohesion in early anaphase, but subsequent Smc3 deacetylation, which is triggered by Scc1 cleavage, is also required.
2017-11-02 | GSE96841 | GEO
Project description:Purpose: We aimed to elucidate the potential mechanisms of effective responsiveness to PD-1 monoclonal antibody and evaluate more reliable biomarkers for improving the predictive utility of the dominant populations of recurrent cervical cancer (RCC) to receive immunotherapy. Methods: Peripheral blood samples of PD-L1 positive patients with RCC treated with second-line PD-1 monoclonal antibody were collected prior to treatment initiation and after the treatment. Differentially expressed genes (DEGs) were analyzed between partial response (PR) patient and progressive disease (PD) patients.
2022-10-05 | GSE205247 | GEO
Project description:The localization of condensin along chromosomes is crucial for their accurate segregation in anaphase. Condensin is enriched at telomeres but how and for what purpose had remained elusive. Here we show that fission yeast condensin accumulates at telomere repeats through the balancing acts of Taz1, a core component of the shelterin complex that ensures telomeric functions, and Mit1, a nucleosome-remodeler associated with shelterin. We further show that condensin takes part in sister-telomere separation in anaphase, and that this event can be uncoupled from the prior separation of chromosomes arms, implying a telomere-specific separation mechanism. Consistent with a cis-acting process, increasing or decreasing condensin occupancy specifically at telomeres modifies accordingly the efficiency of their separation in anaphase. Genetic evidence suggests that condensin promotes sister-telomere separation by counteracting cohesin. Thus, our results reveal a shelterin-based mechanism that enriches condensin at telomeres to drive in cis their separation during mitosis.
2023-10-02 | GSE196149 | GEO
Project description:Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor, but the current therapeutic approaches have very limited impact on increase of the patients’s survival with GBM. Our recent clinical trial with autologous activated nature killer (NK) cells (AKCs) including 14 patients with recurrent GBM found that the progression-free and overall survival times were significantly increased in some patients in the treatment group. In the present study, we identified TNFRSF18, TNFSF4, and IL12RB2 as biomarkers that predict response to NK cell therapeutics by studying the tumor-immune microenvironment using NanoString and qRT-PCR analyses. In addition, our results show that responders to NK therapy have an immune-activated tumor microenvironment, whereas non-responders do not. Considering that immune and inflammatory response-enrichment is related to the high-risk group in this tumor type, our findings highlight a new treatment strategy of NK cell therapeutics for patients with highly aggressive recurrent GBM.
2023-02-01 | GSE207753 | GEO
Project description:RNA-directed DNA methylation (RdDM) plays an essential role in transposable element (TE) silencing in plants. In the Arabidopsis RdDM pathway, the DDR complex containing DRD1, DMS3, and RDM1, is necessary for recruiting Pol V to transcribe scaffold RNA. Although the role of DDR is known, the mechanism by which the DDR complex is regulated remains unexplored. Here, we demonstrate that the Anaphase Promoting Complex/Cyclosome (APC/C) monitors the assembly of the DDR complex by targeting DMS3 for degradation. We show that a subset of Pol V-dependent RdDM loci are de-repressed in apc/c mutants, accompanied by defective recruitment and transcription of Pol V. APC/C targets DMS3 for ubiquitination and degradation in a D box-dependent manner, and the D-box-mutated DMS3 fails to complement the dms3 mutant. Competitive binding assays shows that the dosage of DMS3 is critical for the assembly of the DDR complex, and in vivo gel filtration analysis shows that the assembly of both DDR and Pol V is compromised in the apc8 mutant. These findings uncover a safeguard role of APC/C-mediated DMS3 degradation in the assembly of the DDR complex, and provide a direct link between selective protein degradation and RdDM.
2019-01-31 | GSE106970 | GEO