Cohesin causes replicative DNA damage by trapping DNA topological stress
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PROVIDER: PRJNA544023 | ENA |
REPOSITORIES: ENA
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Project description:DNA topological stress inhibits DNA replication fork (RF) progression and contributes to DNA replication stress. In Saccharomyces cerevisiae we demonstrate that centromeric DNA and the rDNA array are especially vulnerable to DNA topological stress during replication. The activity of the SMC complexes cohesin and condensin are linked to both the generation and repair of DNA topological stress linked damage in these regions. At cohesin enriched centromeres cohesin activity causes the accumulation of DNA damage, RF rotation and precatenation, confirming that cohesin dependent DNA topological stress impacts on normal replication progression. In contrast, at the rDNA cohesin and condensin activity inhibit the repair of damage caused by DNA topological stress. We propose that as well as generally acting to ensure faithful genetic inheritance, SMCs can disrupt genome stability by trapping DNA topological stress.
2020-03-03 | GSE131558 | GEO
Project description: Not available
| S-EPMC7242899 | biostudies-literature
Project description:Cells in culture undergo replicative senescence. In this study, we analyzed functional, genetic and epigenetic sequels of long‐term culture in human mesenchymal stem cells (MSC). Already within early passages the fibroblastoid colony‐ forming unit (CFU‐f) frequency and the differentiation potential of MSC declined significantly. Relevant chromosomal aberrations were not detected by karyotyping and SNP‐microarrays. Subsequently, we have compared DNA‐methylation profiles with the Infinium HumanMethylation27 Bead Array and the profiles differed markedly in MSC derived from adipose tissue and bone marrow. Notably, all MSC revealed highly consistent senescence‐associated modifications at specific CpG sites. These DNA‐methylation changes correlated with histone marks of previously published data sets, such as trimethylation of H3K9, H3K27 and EZH2 targets. Taken together, culture expansion of MSC has profound functional implications ‐ these are hardly reflected by genomic instability but they are associated with highly reproducible DNA‐methylation changes which correlate with repressive histone marks. Therefore replicative senescence seems to be epigenetically controlled. 8 samples of mesenchymal stem cells (MSC) from human adipose tissue
2011-10-27 | E-GEOD-26519 | biostudies-arrayexpress
Project description:The cohesin ring uses its hinge to organize DNA using non-topological as well as topological mechanisms
| PRJNA414408 | ENA
Project description:Cells in culture undergo replicative senescence. In this study, we analyzed functional, genetic and epigenetic sequels of long‐term culture in human mesenchymal stem cells (MSC). Already within early passages the fibroblastoid colony‐ forming unit (CFU‐f) frequency and the differentiation potential of MSC declined significantly. Relevant chromosomal aberrations were not detected by karyotyping and SNP‐microarrays. Subsequently, we have compared DNA‐methylation profiles with the Infinium HumanMethylation27 Bead Array and the profiles differed markedly in MSC derived from adipose tissue and bone marrow. Notably, all MSC revealed highly consistent senescence‐associated modifications at specific CpG sites. These DNA‐methylation changes correlated with histone marks of previously published data sets, such as trimethylation of H3K9, H3K27 and EZH2 targets. Taken together, culture expansion of MSC has profound functional implications ‐ these are hardly reflected by genomic instability but they are associated with highly reproducible DNA‐methylation changes which correlate with repressive histone marks. Therefore replicative senescence seems to be epigenetically controlled.
2011-10-28 | GSE26519 | GEO
Project description:As predicted by the notion that sister chromatid cohesion is mediated by entrapment of sister DNAs inside cohesin rings, there is a perfect correlation between co-entrapment of circular minichromosomes and sister chromatid cohesion. In most cells where cohesin loads onto chromosomes but fails to form cohesion, loading is accompanied by entrapment of individual DNAs. However, cohesin with a hinge whose positively charged lumen has been neutralized not only loads onto and translocates along chromatin but also organizes it into chromatid-like threads, despite largely failing to entrap DNAs inside its ring. Thus, cohesin engages chromatin in both a non-topological and a topological manner. Further, mutation of three highly conserved lysines within the Smc1 hinge abolishes all loading without affecting cohesin’s initial recruitment to centromers or its ability to hydrolyze ATP. We suggest that loading and translocation are mediated by conformational changes in cohesin’s hinge driven by cycles of ATP hydrolysis.
2018-04-23 | GSE105005 | GEO
Project description:The ring-shaped cohesin complex is thought to fulfil its roles in sister chromatid cohesion, genome stability and gene regulation by topologically encircling DNAs. The ring is formed by two Structural Maintenance of Chromosome (SMC) subunits, whose ATPase heads are linked by a kleisin subunit. Additional components, including the Mis4Scc2/NIPL cohesin loader, engage the kleisin. Here, we visualize a DNA gripping intermediate during cohesin loading onto DNA by cryo-electron microscopy. ATP-dependent head engagement creates an interaction surface onto which Mis4Scc2/NIPL clamps the DNA. We use biophysical tools to establish the order of events during cohesin loading. DNA first traverses an N-terminal kleisin gate that was opened by ATP binding and closed again as the loader locks the DNA. Ensuing ATP hydrolysis and head disengagement, assisted by Mis4Scc2/NIPL, will complete DNA entry. A conserved kleisin N-terminal tail guides the DNA on its trajectory to successful topological DNA entry into the cohesin ring.
2020-08-05 | PXD018600 | Pride
Project description:The cohesin complex is mutated in cancer and in a number of rare familiar syndromes collectively known as Cohesinopathies. In the latter case, cohesin deficiencies have been linked to transcriptional alterations affecting Myc and its target genes. Here, we set out to understand to what extent the role of cohesins in controlling cell cycle is dependent on Myc expression and activity. Inactivation of the cohesin complex by silencing the RAD21 subunit led to cell cycle arrest due to both transcriptional impairment of Myc target genes and alterations of replication forks, which were fewer and preferentially unidirectional. Ectopic activation of Myc in RAD21 depleted cells, fully rescued transcription and promoted S-phase entry but failed to sustain S-phase progression thus leading to a strong replicative stress response, which was associated to a robust DNA damage response, DNA damage checkpoint activation and synthetic lethality. Thus, the cohesin complex is dispensable for Myc dependent transcription but essential to prevent Myc induced replicative stress. This suggests the presence of a topological checkpoint orchestrated by cohesins that by regulating Myc level prevents S-phase entry and replicative stress in cohesion compromised cells.
2017-12-22 | GSE89799 | GEO
Project description:We demonstrate that transcriptomic profiling of the NER mutant ercc-1 offers better understanding of the complex phenotypes of ercc-1 deficiency in C. elegans, as it does in mammalian models. There is a transcriptomic shift in ercc-1 mutants that suggests a stochastic impairment of growth and development, with a shift towards a higher proportion of males in the population. Extensive phenotypic analyses confirm that NER deficiency in C. elegans leads to severe developmental and growth defects and a reduced replicative lifespan, although post-mitotic lifespan is not affected. Results suggest that these defects are caused by an inability to cope with randomly occurring DNA damage, which may interfere with transcription and replication. The study investigates the developmental and aging phenotypes of different NER deficient C. elegans mutants (xpa-1, ercc-1, xpf-1 and xpg-1), where the transcriptomic profile of ercc-1 mutant is presented. We show that loss of NER function does not affect post-mitotic lifespan, but leads to impaired embryogenesis, germ cell and larval development and causes a reduced replicative lifespan. Phenotypes are most pronounced in ercc-1, xpf-1 and xpg-1 mutant animals. We provide evidence that this more pronounced phenotype is likely caused by the fact that these genes are involved in multiple repair pathways besides NER. Furthermore, transcriptional profiling of ercc-1 mutants confirms these observations, showing that growth and developmental pathways are underrepresented but that insulin signaling is not affected. Our analysis suggests that XPA-1, ERCC-1, XPF-1 and XPG-1 protect animals against replicative aging by preventing the accumulation of randomly acquired DNA damage. Eight mixed stage C. elegans samples were run on Affymetrix GeneChip C. elegans Genome Arrays. Four samples belong to ercc-1 mutant group and four to the wild-type, N2.
2013-09-15 | E-GEOD-39145 | biostudies-arrayexpress
Project description:Setdb1 regulates Cohesin at H3K9me3-independent topological domains
| PRJNA507948 | ENA