DNA damage tolerance branches out toward sister chromatid cohesion.
Ontology highlight
ABSTRACT:
SUBMITTER: Branzei D
PROVIDER: S-EPMC4845193 | biostudies-other | 2016 Jan
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Newly copied sister chromatids are tethered together by the cohesin complex, but how sister chromatid cohesion coordinates with DNA replication is poorly understood. Prevailing models suggest that cohesin complexes, bound to DNA before replication, remain behind the advancing replication fork to keep sister chromatids together. By visualizing single replication forks colliding with preloaded cohesin complexes, we find that the replisome instead pushes cohesin to where a converging replisome is met. Whereas the converging replisomes are removed during DNA replication termination, cohesin remains on nascent DNA and provides cohesion. Additionally, we show that CMG (CDC45-MCM2-7-GINS) helicase disassembly during replication termination is vital for proper cohesion in budding yeast. Together, our results support a model wherein sister chromatid cohesion is established during DNA replication termination.
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Project description:Cohesion between sister chromatids is established during DNA replication but needs to be maintained to enable proper chromosome-spindle attachments in mitosis or meiosis. Cohesion is mediated by cohesin, but also depends on cohesin acetylation and sororin. Sororin contributes to cohesion by stabilizing cohesin on DNA. Sororin achieves this by inhibiting WAPL, which otherwise releases cohesin from DNA and destroys cohesion. Here we describe mouse models which enable the controlled depletion of sororin by gene deletion or auxin-induced degradation. We show that sororin is essential for embryonic development, cohesion maintenance, and proper chromosome segregation. We further show that the acetyltransferases ESCO1 and ESCO2 are essential for stabilizing cohesin on chromatin, that their only function in this process is to acetylate cohesin's SMC3 subunit, and that DNA replication is also required for stable cohesin-chromatin interactions. Unexpectedly, we find that sororin interacts dynamically with the cohesin complexes it stabilizes. This implies that sororin recruitment to cohesin does not depend on the DNA replication machinery or process itself, but on a property that cohesin acquires during cohesion establishment.
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Project description:Eukaryotic genomes are folded into DNA loops mediated by SMC complexes, like cohesin, condensin and Smc5/6. This organization regulates different DNA related processes along the cell cycle such as transcription, recombination, segregation and DNA repair. During G2/M phases, SMC complexes mediated DNA loops coexist with cohesin complexes involved in sister chromatid cohesion (SCC). It remains unknown whether SCC and DNA loop expansion influence each other and if they cooperate to regulate DNA-related processes. Here we show that SCC is indeed a barrier to DNA loop expansion mediated by cohesin in G2.
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Project description:Accurate chromosome segregation depends on sister kinetochores making bioriented attachments to microtubules from opposite poles. An essential regulator of biorientation is the Ipl1/Aurora B protein kinase that destabilizes improper microtubule-kinetochore attachments. To identify additional biorientation pathways, we performed a systematic genetic analysis between the ipl1-321 allele and all nonessential budding yeast genes. One of the mutants, mcm21Delta, precociously separates pericentromeres and this is associated with a defect in the binding of the Scc2 cohesin-loading factor at the centromere. Strikingly, Mcm21 becomes essential for biorientation when Ipl1 function is reduced, and this appears to be related to its role in pericentromeric cohesion. When pericentromeres are artificially tethered, Mcm21 is no longer needed for biorientation despite decreased Ipl1 activity. Taken together, these data reveal a specific role for pericentromeric linkage in ensuring kinetochore biorientation.
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Project description:Long noncoding RNAs (lncRNAs) are involved in diverse cellular processes through multiple mechanisms. Here, we describe a previously uncharacterized human lncRNA, CONCR (cohesion regulator noncoding RNA), that is transcriptionally activated by MYC and is upregulated in multiple cancer types. The expression of CONCR is cell cycle regulated, and it is required for cell-cycle progression and DNA replication. Moreover, cells depleted of CONCR show severe defects in sister chromatid cohesion, suggesting an essential role for CONCR in cohesion establishment during cell division. CONCR interacts with and regulates the activity of DDX11, a DNA-dependent ATPase and helicase involved in DNA replication and sister chromatid cohesion. These findings unveil a direct role for an lncRNA in the establishment of sister chromatid cohesion by modulating DDX11 enzymatic activity.
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Project description:Cohesin is a multi-subunit protein complex essential for sister chromatid cohesion, gene expression and DNA damage repair. Although structurally well studied, the underlying determinant of cohesion establishment on chromosomal arms remains enigmatic. Here, we show two populations of functionally distinct cohesin on chromosomal arms using a combination of genomics and single-locus specific DNA-FISH analysis. Chromatin bound cohesin at the loading sites co-localizes with Pds5 and Eso1 resulting in stable cohesion. In contrast, cohesin independent of its loader is unable to maintain cohesion and associates with chromatin in a dynamic manner. Cohesive sites coincide with highly expressed genes and transcription inhibition leads to destabilization of cohesin on chromatin. Furthermore, induction of transcription results in de novo recruitment of cohesive cohesin. Our data suggest that transcription facilitates cohesin loading onto chromosomal arms and is a key determinant of cohesive sites in fission yeast.
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Project description:The response to DNA damage in vertebrate cells involves successive recruitment of DNA signalling and repair factors. We used light microscopy to monitor the genetic dependencies of such localization to a single, induced DNA double strand break (DSB) in vertebrate cells. We used an inducible version of the rare-cutting I-SceI endonuclease to cut a chromosomally integrated I-SceI site beside a Tet operator array that was visualized by binding a Tet repressor-GFP fusion. Formation of gamma-H2AX foci at a single DSB was independent of ATM or Ku70. ATM-deficient cells showed normal kinetics of 53Bp1 recruitment to DSBs, but Rad51 localization was retarded. 53Bp1 and Rad51 foci formation at a single DSB was greatly reduced in H2AX-null DT40 cells. We also observed decreased inter-sister chromatid distances after DSB induction, suggesting that cohesin loading at DSBs causes elevated sister chromatid cohesion. Loss of ATM reduced DSB-induced cohesion, consistent with cohesin being an ATM target in the DSB response. These data show that the same genetic pathways control how cells respond to single DSBs and to multiple lesions induced by whole-cell DNA damage.
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Project description:Cohesion between sister chromatids depends on the chromosomal cohesin complex and allows the spindle apparatus in mitosis to recognize replicated chromosomes for segregation into daughter cells. Sister chromatid cohesion is established concomitant with DNA replication, and requires the essential Eco1 protein, a replication fork-associated acetyl transferase. The mechanism by which Eco1 establishes sister chromatid cohesion is not known. Here, we show that the cohesin subunit Smc3 is acetylated in an Eco1-dependent manner during S phase to establish sister chromatid cohesion. We isolated spontaneous suppressors of the thermosensitive eco1-1 allele in budding yeast, and identified the suppressor mutations from the hybridization pattern of genomic DNA on oligonucleotide tiling arrays. An acetylation mimicking mutation of a conserved lysine in Smc3 to asparagine (K113N) makes Eco1 dispensable for cell growth, indicating that Smc3 acetylation is Eco1’s only essential function. We identified a second set of eco1-1 suppressor mutations in the budding yeast ortholog of the cohesin regulator Wapl (Wpl1/Rad61). Wapl destabilizes cohesin on chromosomes, and Eco1-dependent Smc3 acetylation during S-phase might render cohesin resistant to Wapl. Our results clarify the role of Eco1 in the establishment of sister chromatid cohesion, and suggest that Eco1 modifies cohesin to stabilize an Eco1-independent cohesion establishment reaction.
2008-07-24 | GSE11527 | GEO
Project description:Sister chromatid cohesion halts DNA loop expansion
| PRJNA993572 | ENA