Swc4 protects chromatin against genome instability and aneuploidy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA778198 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16816505_1.fastq.gz | Fastqsanger.gz | |||
| SRR16816505_2.fastq.gz | Fastqsanger.gz | |||
| SRR16816506_1.fastq.gz | Fastqsanger.gz | |||
| SRR16816506_2.fastq.gz | Fastqsanger.gz | |||
| SRR16816507_1.fastq.gz | Fastqsanger.gz |
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Project description:In the baker’s yeast Saccharomyces cerevisiae, Swc4, Yaf9, Arp4, and Act1 form a submodule shared by histone acetylation NuA4 complex and chromatin remodeling SWR1 complex (SWR1-C). Act1 and Arp4 are essential for cell survival. Deletion of SWC4, but not YAF9, results in severe growth defect, however, the underlying mechanism remains largely unknown. Here, we show that swc4Δ, but not yaf9Δ, eaf1Δ, or swr1Δ cells display mitotic defects in both faithful chromosome segregation and DNA ploidy, suggesting that the defects observed in swc4Δ cells are independent of the integrity of either NuA4 or SWR1-C. Additionally, loss of Swc4 function results in chromosomal breakage, spindle assembly check-point activation and significant increase of the Rfa1 foci and γ-H2A levels. Notably, both telomeres and rDNA loci in swc4Δ cells become unstable and are highly susceptible to recombination. Mechanistically, Swc4 interacts with chromatin likely through hypoacetylated histone H4. Taking together, we conclude that the chromatin associated Swc4 protects chromatin from breakage to ensure genome integrity.
2021-11-07 | GSE188281 | GEO
Project description:Chromosome aneuploidy increases in oocytes with maternal age, and is considered the leading cause for the increased incidence of infertility, miscarriage, and birth defects. Using mRNA-Sequencing of oocytes from 12 month old mouse versus 3 month young mouse, we identified a spindle assembly checkpoint gene, BubR1, whose expression was significantly decreased. We employed a mRNA microinjection based approach to increase BubR1 expression in aging oocytes. We find that increased expression of BubR1 protects against aneuploidy and chromosome misalignment in aging oocytes. After in vitro fertilization, the embryos derived from BubR1 increased expression aging oocytes exhibited chromosome stability as robust as those of the young ones. Furthermore, following embryo transfer, these embryos showed greatly improved developmental competency, with comparable levels of full-term development to those of the young ones. These results indicate that the decline in oocyte quality may be reversible and could lead to treatments that prolong female fertility. Examination of the effect of maternal aging on the mRNA expression in the mature oocytes of the female mice. Naturally ovulated mature oocytes (MII stage) were collected from 6 young (3 month) and 6 aging (12 month) female mice (3 oocytes per mice, 18 oocytes for each group).
2014-05-10 | E-GEOD-57482 | biostudies-arrayexpress
Project description:Chromosome aneuploidy increases in oocytes with maternal age, and is considered the leading cause for the increased incidence of infertility, miscarriage, and birth defects. Using mRNA-Sequencing of oocytes from 12 month old mouse versus 3 month young mouse, we identified a spindle assembly checkpoint gene, BubR1, whose expression was significantly decreased. We employed a mRNA microinjection based approach to increase BubR1 expression in aging oocytes. We find that increased expression of BubR1 protects against aneuploidy and chromosome misalignment in aging oocytes. After in vitro fertilization, the embryos derived from BubR1 increased expression aging oocytes exhibited chromosome stability as robust as those of the young ones. Furthermore, following embryo transfer, these embryos showed greatly improved developmental competency, with comparable levels of full-term development to those of the young ones. These results indicate that the decline in oocyte quality may be reversible and could lead to treatments that prolong female fertility.
2014-05-10 | GSE57482 | GEO
Project description:Aneuploidy promotes genomic instability by impairing DNA replication
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Project description:Aneuploidy, while detrimental to untransformed cells, is notably prevalent in cancer. Aneuploidy is found as an early event during tumorigenesis which indicates that cancer cells have the ability to surmount the initial stress responses associated with aneuploidy, enabling rapid proliferation despite aberrant karyotypes. To generate more insight into key cellular processes and requirements underlying adaptation to aneuploidy, we generated a panel of aneuploid clones in p53-deficient RPE-1 cells and studied their behavior over time. As expected, de novo generated aneuploid clones initially displayed reduced fitness, enhanced levels of chromosomal instability and an upregulated inflammatory response. Intriguingly, after a prolonged period of culturing, aneuploid clones exhibited increased proliferation rates while maintaining aberrant karyotypes, indicative of an adaptive response to the aneuploid state. Interestingly, all adapted clones displayed reduced chromosomal instability (CIN) and reduced inflammatory signaling, suggesting that these are common aspects of adaptation to aneuploidy. Collectively, our data suggests that CIN and concomitant inflammation are key processes that require correction to allow for fast proliferation in vitro. Finally, we provide evidence that amplification of oncogenic KRAS can promote adaptation.
2024-08-12 | GSE273576 | GEO
Project description:HIRA protects telomeres against R-loop-induced instability in ALT cancer cells [ATAC-seq]
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Project description:HIRA protects telomeres against R-loop-induced instability in ALT cancer cells [CUT&RUN]
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Project description:Chromatin rewiring mediates programmed evolvability via aneuploidy
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Project description:In Saccharomyces cerevisiae, Elevated Levels of Aneuploidy and Chromosome Rearrangements are Separable Genome Instability Events Controlled by the Tel1 and Mec1 Kinases Cancer cells often have elevated frequencies of chromosomal aberrations, and it is likely that loss of genome stability is one driving force behind tumorigenesis. Deficiencies in DNA replication, DNA repair, or cell cycle checkpoints can all contribute to increased rates of chromosomal duplications, deletions and translocations. The Saccharomyces cerevisiae proteins Tel1 and Mec1 (homologues of the human ATM and ATR proteins, respectively) are known to participate in the DNA damage response, replication checkpoint, and telomere maintenance pathways and are critical to maintain genome stability. In the absence of induced DNA damage, tel1 mec1 diploid yeast strains exhibit extremely high rates of chromosome aneuploidy. There is a significant bias towards trisomy of chromosomes II, VIII, X, and XII, whereas the smallest chromosomes I and VI are commonly monosomic. tel1 mec1 strains also demonstrate elevated levels of chromosome rearrangements, including translocations as well as interstitial duplications and deletions. Restoring wild-type telomere length with the Cdc13-Est2 fusion protein substantially reduces the amount of chromosome rearrangements in tel1 mec1 strains. This result suggests that most of the rearrangements are initiated by telomere-telomere fusions. However, the telomere defects associated with tel1 mec1 strains do not cause the high rate of aneuploidy, as restoring proper telomere function does not prevent cells from becoming aneuploid. Our data demonstrate that the same mutant genotype can produce both high levels of chromosome rearrangements and high levels of aneuploidy, and these two types of events occur through separate mechanisms.
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Project description:Eukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis, and yet specific aneuploidies can be adaptive during environmental stress. Here, we identify a chromatin-based system for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire resistance to antifungal drugs and for ploidy reduction after mating. We discovered that the ancestor of C. albicans and two related pathogens evolved a variant of histone H2A that lacks the conserved phosphorylation site for Bub1 kinase, a key regulator of chromosome segregation. Using engineered strains, we show that expression of this variant controls the rates of aneuploidy and antibiotic resistance in this species. Moreover, whole genome chromatin precipitation analysis reveals that CENP-A/Cse4, the histone H3 that specifies centromeres, is depleted from tetraploid mating products and virtually eliminated from cells exposed to aneuploidy-promoting cues. Thus, changes in chromatin regulation can confer the capacity for rapid evolution in eukaryotes.
2019-05-23 | GSE122037 | GEO