Genetic variation in the anaphase promoting complex modulates fertility and chromosome alignment defects in the absence of KIF18A
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1182387 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31235529_1.fastq.gz | Fastqsanger.gz | |||
| SRR31235529_2.fastq.gz | Fastqsanger.gz | |||
| SRR31235530_1.fastq.gz | Fastqsanger.gz | |||
| SRR31235530_2.fastq.gz | Fastqsanger.gz | |||
| SRR31235531_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 120 |
Similar Datasets
Project description:The kinesin family member 18A (Kif18a) is an essential regulator of microtubule dynamics and chromosome alignment during mitosis. Laboratory mice with a loss of function mutation in Kif18a are are infertile due to mitotic arrest of germ cells, but this phenotype shows variable penetrance depending on genetic background. Kif18a is also necessary for mitotic progression of chromosomally unstable cancer cells, which exhibit mitotic arrest in the absence of KIF18A function. While it is clear that functional dependency on KIF18A varies by cell type and genetic context, the heritable factors that influence this dependency remain unknown. To address this, we took advantage of the variable penetrance observed in different mouse strain backgrounds to screen for genetic loci that modulate germ cell depletion in the absence of KIF18A. We found a significant association between the severity of germ cell depletion and a locus on Chr5 wherein anaphase promoting complex subunits 5 (Anapc5) and 7 (Anapc7) were the top candidate genes. We compared the expression of both genes at key timepoints in gondal development and found that both genes were differentially expressed in sensitive strain backgrounds when compared to resistant strain backgrounds. We also identify a novel retroviral insertion in Anapc7 that may in part explain the observed expression differences. In cell line models, we found that depletion of KIF18A induced mitotic arrest, which was partially rescued by co-depletion of APC7 and exacerbated by co-depletion of APC5. These findings suggest that differential expression and activity of Anapc5 and Anapc7 may influence sensitivity to KIF18A depletion in germ cells and CIN cells, with potential implications for optimizing antineoplastic therapies.
2024-12-02 | GSE281149 | GEO
Project description:Anaphase-promoting complex-dependent control of cell identity
| PRJNA504508 | ENA
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:Chromosome alignment at the equator of the mitotic spindle is a highly conserved step during cell division; however, its importance to genomic stability and cellular fitness is not understood. Normal mammalian somatic cells lacking KIF18A function complete cell division without aligning chromosomes. These alignment-deficient cells display normal chromosome copy numbers in vitro and in vivo, suggesting that chromosome alignment is largely dispensable for maintenance of euploidy. However, we find that loss of chromosome alignment leads to interchromosomal compaction defects during anaphase, abnormal organization of chromosomes into a single nucleus at mitotic exit, and the formation of micronuclei in vitro and in vivo. These defects slow cell proliferation and are associated with impaired postnatal growth and survival in mice. Our studies support a model in which the alignment of mitotic chromosomes promotes proper organization of chromosomes into a single nucleus and continued proliferation by ensuring that chromosomes segregate as a compact mass during anaphase.
| S-EPMC6446859 | biostudies-literature
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:RNA-seq read alignment evaluation
| PRJEB4265 | ENA
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: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:Clinical treatment responsiveness in recurrent canine lymphoma correlates with Anaphase Promoting Complex activity
| PRJNA496432 | ENA
Project description:In C. elegans, mutants in the anaphase-promoting complex or cyclosome (APC/C) exhibit defects in germline proliferation, the formation of the vulva and male tail, and the metaphase to anaphase transition of meiosis I. Oocytes lacking APC/C activity can be fertilized but arrest in metaphase of meiosis I and are blocked from further development. To examine the cell cycle and developmental consequences of reducing but not fully depleting APC/C activity, we analyzed defects in embryos and larvae of mat-1/cdc-27 mutants grown at semi-permissive temperatures. Hypomorphic embryos developed to the multicellular stage but were slow to complete meiosis I and displayed aberrant meiotic chromosome separation. More severely affected embryos skipped meiosis II altogether and exhibited striking defects in meiotic exit. These latter embryos failed to produce normal eggshells or establish normal asymmetries prior to the first mitotic division. In developing larvae, extended M-phase delays in late-dividing cell lineages were associated with defects in the morphogenesis of the male tail. This study reveals the importance of dosage-specific mutants in analyzing molecular functions of a ubiquitously functioning protein within different cell types and tissues, and striking correlations between specific abnormalities in cell cycle progression and particular developmental defects.
| S-EPMC1805483 | biostudies-literature