Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA321436 | ENA |
REPOSITORIES: ENA
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Project description:Near-tetraploid cells exhibit chromosome instability triggered by replication stress and enhanced invasive capabilities
| PRJNA321435 | ENA
Project description:Near-tetraploid cells exhibit chromosome instability triggered by replication stress and enhanced invasive capabilities [aCGH]
| PRJNA321437 | ENA
Project description:A considerable proportion of tumors exhibit aneuploid karyotypes, likely resulting from the loss of chromosomes following whole genome duplication. Here, by using isogenic diploid and near-tetraploid clones derived from the same parental cell line, we aimed at exploring how polyploidization affects cellular functions and how tetraploidy generates chromosome instability. Gene expression profiling in near-tetraploid clones revealed a significant enrichment of genes involved in replication stress. This increased level of replication stress resulted in DNA damage, greater sensitivity to S-phase checkpoint inhibitors, and impaired proliferation caused by a cell cycle delay during S-phase. Additionally, replication stress promoted higher levels of intercellular heterogeneity and ongoing genomic instability, which we observed in the form of abnormal anaphases and prometaphase events. Finally, our data unveiled that near-tetraploid cells displayed increased migratory and invasive capacities, both in vitro and in primary colorectal tumors, thus providing physiological advantages to the cancer cell.
2017-05-10 | GSE81394 | GEO
Project description:A considerable proportion of tumors exhibit aneuploid karyotypes, likely resulting from the loss of chromosomes following whole genome duplication. Here, by using isogenic diploid and near-tetraploid clones derived from the same parental cell line, we aimed at exploring how polyploidization affects cellular functions and how tetraploidy generates chromosome instability. Gene expression profiling in near-tetraploid clones revealed a significant enrichment of genes involved in replication stress. This increased level of replication stress resulted in DNA damage, greater sensitivity to S-phase checkpoint inhibitors, and impaired proliferation caused by a cell cycle delay during S-phase. Additionally, replication stress promoted higher levels of intercellular heterogeneity and ongoing genomic instability, which we observed in the form of abnormal anaphases and prometaphase events. Finally, our data unveiled that near-tetraploid cells displayed increased migratory and invasive capacities, both in vitro and in primary colorectal tumors, thus providing physiological advantages to the cancer cell.
2017-05-10 | GSE81303 | GEO
Project description:Mammalian Bre1 complexes (BRE1A/B (RNF20/40) in humans and Bre1a/b (Rnf20/40) in mice) function similarly to their yeast homolog Bre1 as ubiquitin ligases in monoubiquitination of histone H2B. This ubiquitination facilitates methylation of histone H3 at K4 and K79, and accounts for the roles of Bre1 and its homologs in transcriptional regulation. Recent studies by others suggested that Bre1 acts as a tumor suppressor, augmenting expression of select tumor suppressor genes and suppressing select oncogenes. In this study we present an additional mechanism of tumor suppression by Bre1 through maintenance of genomic stability. We track the evolution of genomic instability in Bre1-deficient cells from replication-associated double-strand breaks (DSBs) to specific genomic rearrangements that explain a rapid increase in DNA content and trigger breakage-fusion-bridge cycles. We show that aberrant RNA-DNA structures (R-loops) constitute a significant source of DSBs in Bre1-deficient cells. Combined with a previously reported defect in homologous recombination, generation of R-loops is a likely initiator of replication stress and genomic instability in Bre1-deficient cells. We propose that genomic instability triggered by Bre1 deficiency may be an important early step that precedes acquisition of an invasive phenotype, as we find decreased levels of BRE1A/B and dimethylated H3K79 in testicular seminoma and in the premalignant lesion in situ carcinoma. A cellular modification design type is where a modification of the transcriptome, proteome (not genome) is made, for example RNAi, antibody targeting. Knock down by RNA interference: gene knocked down in RIF-1 cell line cellular_modification_design
2013-01-09 | E-GEOD-34977 | biostudies-arrayexpress
Project description:DNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineered genetic systems in budding yeast to induce unscheduled replication in the G1-phase of the cell cycle. Unscheduled G1 replication initiated at canonical S-phase origins. We quantified the composition of replisomes in G1- and S-phase and identified firing factors, polymerase alpha, and histone supply as factors that limit replication outside S-phase. G1 replication per se did not trigger cellular checkpoints. Subsequent replication during S-phase, however, resulted in over-replication and led to chromosome breaks and chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA indicating head-to-tail replication collisions as a key mechanism generating genome instability upon G1 replication. Low-level, sporadic induction of G1 replication induced an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation.
2022-11-08 | GSE208589 | GEO
Project description:We used isobaric tags for relative and absolute quantitation (iTRAQ) to perform a quantitative proteomic analysis of immature spikes harvested from tetraploid near-isogenic lines of wheat with normal spikelete (NSs), FRSs, and RSs and investigated the molecular mechanisms of lateral meristem differentiation and development. This work provides valuable insight into the underlying functions of the lateral meristem and how it can produce differences in the branching of tetraploid wheat spikes.
2018-10-19 | PXD008910 | Pride
Project description:It is well-known that embryonic stem cells (ESC) are much more sensitive to replication-induced stress than differentiated cells but the underpinning mechanisms are largely unknown. H2A.X, a minor variant of H2A, constitutes only 1-10% of the mammalian genome. H2A.X plays a well-known for role in the DNA damage response and maintaining stability in the genome, including the regions frequently experiencing replication stress, such as the fragile sites. Intriguingly, several recent studies have reported that H2A.X function is elevated in ESC; and others reported that H2A.X function is provoked during cellular reprogramming (in induced pluripotent stem cells, iPSC), indicating that increased proliferation during iPS may trigger replication stress and the H2A.X DNA damage response. However, several studies of genomic instability in iPSC led to different conclusions on this important issue. For example, frequent copy number variants (CNV) were reported at the genomic regions sensitive to replication stress, such as the fragile sites. On the other hand, another study reported the lack of genomic instability in mouse iPS clones that are able to generate “all-iPS” animals in tetraploid complementation assays (4N+ iPSC), indicative of a potential link between pluripotency and genome integrity. However, whether if high level genomic instability occurs in the 4N- iPSC iPSC clones at replication stress sensitive regions is unknown. Moreover, due to the lack of mechanistic insights on genome integrity maintenance, how pluripotency and genome integrity are connected remains elusive. Here we show that H2A.X plays unexpected roles in maintaining pluripotency and genome integrity in ESC and iPSC. In ESC, it is specially enriched at genomic regions sensitive to replication stress so that it protects genome integrity thereat. Faithful H2A.X deposition is critical for genome integrity and pluripotency in iPSC. H2A.X depositions in 4N+ iPSC clones faithfully recapitulate the ESC pattern and therefore, prevent genome instability. On the other hand, insufficient H2A.X depositions in 4N- iPSC clones at such regions lead to genome instability and defects in replication stress response and DNA repair, reminiscent of the H2A.X deficient ESC. Detect and compare different H2A.X deposition patterns in ES cells and iPS cells, with Illumina HiSeq 2000 and Illumina Genome Analyzer IIx
2014-09-07 | E-GEOD-42306 | biostudies-arrayexpress
Project description:DNA replication stress (DRS)-linked genomic instability has emerged as an important factor driving cancer development. To understand the mechanisms of DRS-associated genomic instability and phenotypic evolution, we mapped chromosomal alterations in a yeast strain with lowered expression of the replicative DNA polymerase δ. At a whole-genome level, we identified both hotspots of mitotic recombination and chromosome-specific aneuploidy dependent on decreased levels of DNA polymerase δ. The high rate of chromosome loss is likely a reflection of reduced DNA repair capacity in strains with low levels of DNA polymerase. Most recombinogenic DNA lesions were introduced during S or G2 phase, presumably as a consequence of broken replication forks.
2016-03-03 | GSE78856 | GEO
Project description:Human pluripotent stem cells (hPSCs) tend to acquire chromosomal aberrations in culture, which may increase their tumorigenicity. However, the cellular mechanism(s) underlying these aberrations are largely unknown. Here we show that the DNA replication in aneuploid hPSCs is perturbed, resulting in high prevalence of defects in chromosome condensation and segregation. Global gene expression analyses in aneuploid hPSCs revealed decreased levels of actin cytoskeleton genes and their common transcription factor SRF. Down-regulation of SRF or chemical perturbation of actin cytoskeleton organization in diploid hPSCs resulted in increased replication stress and perturbation of chromosome condensation, recapitulating the findings in aneuploid hPSCs. Altogether, our results revealed that in hPSCs DNA replication stress results in a distinctive defect in chromosome condensation, underlying their ongoing chromosomal instability. Our results shed a new light on the mechanisms leading to ongoing chromosomal instability in hPSCs, and may be relevant to tumor development as well. Expression data from diploid human pluripotent stem cells Total RNA was isolated from undifferentiated human pluripotent stem cells grown under standard human ES conditions or under condition media
2015-11-12 | E-GEOD-64647 | biostudies-arrayexpress