Cohesin: a catenase with separate entry and exit gates?
TL;DR: It is suggested that the ring's entry and exit gates may be separate, with the former and latter taking place at Smc1–Smc3 and Smc3–kleisin interfaces, respectively, and establishment of cohesion during S phase involves neutralization of releasin through acetylation of Smc2 at a site close to the putative exit gate of DNA.
Abstract: Cohesin confers both intrachromatid and interchromatid cohesion through formation of a tripartite ring within which DNA is thought to be entrapped. Here, I discuss what is known about the four stages of the cohesin ring cycle using the ring model as an intellectual framework. I postulate that cohesin loading onto chromosomes, catalysed by a separate complex called kollerin, is mediated by the entry of DNA into cohesin rings, whereas dissociation, catalysed by Wapl and several other cohesin subunits (an activity that will be called releasin here), is mediated by the subsequent exit of DNA. I suggest that the ring's entry and exit gates may be separate, with the former and latter taking place at Smc1–Smc3 and Smc3–kleisin interfaces, respectively. Establishment of cohesion during S phase involves neutralization of releasin through acetylation of Smc3 at a site close to the putative exit gate of DNA, which locks rings shut until opened irreversibly by kleisin cleavage through the action of separase, an event that triggers the metaphase to anaphase transition.
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TL;DR: In this paper, the authors discuss the importance of chromatin structure and organization in eukaryotic genomes and their importance in maintaining the integrity of both genome and epigenome integrity with severe consequences for the organism.
Abstract: Stability and function of eukaryotic genomes are closely linked to chromatin structure and organization. During cell division the entire genome must be accurately replicated and the chromatin landscape reproduced on new DNA. Chromatin and nuclear structure influence where and when DNA replication initiates, whereas the replication process itself disrupts chromatin and challenges established patterns of genome regulation. Specialized replication-coupled mechanisms assemble new DNA into chromatin, but epigenome maintenance is a continuous process taking place throughout the cell cycle. If DNA synthesis is perturbed, cells can suffer loss of both genome and epigenome integrity with severe consequences for the organism.
509 citations
TL;DR: Stability and function of eukaryotic genomes are closely linked to chromatin structure and organization, and if DNA synthesis is perturbed, cells can suffer loss of both genome and epigenome integrity with severe consequences for the organism.
Abstract: Stability and function of eukaryotic genomes are closely linked to chromatin structure and organization During cell division the entire genome must be accurately replicated and the chromatin landscape reproduced on new DNA Chromatin and nuclear structure influence where and when DNA replication initiates, whereas the replication process itself disrupts chromatin and challenges established patterns of genome regulation Specialized replication-coupled mechanisms assemble new DNA into chromatin, but epigenome maintenance is a continuous process taking place throughout the cell cycle If DNA synthesis is perturbed, cells can suffer loss of both genome and epigenome integrity with severe consequences for the organism
493 citations
TL;DR: The binding pattern of expressed TFs in human colorectal cancer cells is analyzed and it is found that binding of TFs is highly clustered and that the clusters are enriched in binding motifs for several major TF classes.
332 citations
Cites background from "Cohesin: a catenase with separate e..."
...Its name comes from its first identified function, the establishment of cohesion between sister chromosomes (Nasmyth, 2011; Sherwood et al., 2010)....
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...…and insulator markers (modified and variant histones, p300), three subunits of cohesin (SMC1A, SMC3, and RAD21), the cohesin loading factor NIPBL, twomediator subunits (MED1, MED12), and CTCF (Rollins et al., 1999; Heintzman et al., 2007; Visel et al., 2009; Kagey et al., 2010; Nasmyth, 2011)....
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TL;DR: This Review surveys both conserved features and rich variations of condensin-based chromosome organization and discusses their evolutionary implications.
325 citations
Cites background from "Cohesin: a catenase with separate e..."
...It will also be of importance to determine whether condensins’ hinge could transiently ‘‘split’’ to allow DNA’s entry into the inter-arm space, as has been proposed for the action of cohesins (Nasmyth, 2011)....
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...Cohesins have specialized loading and unloading factors (Nasmyth, 2011), whereas no corresponding factors dedicated to condensins have been identified thus far....
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...Accumulating lines of evidence during the past years have substantiated the idea that cohesins topologically entrap DNA strands within their ring-like structure (Nasmyth, 2011)....
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...Comparing and Contrasting Condensins and Cohesins Cohesins, another representative class of eukaryotic SMC protein complexes, play a central role in sister chromatid cohesion during mitosis and meiosis (Nasmyth, 2011)....
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TL;DR: The in vitro reconstitution of cohesin loading onto DNA provides mechanistic insight into the initial steps of the establishment of sister chromatid cohesion and other chromosomal processes mediated by cohesIn, purified fission yeast cohes in and its loader complex are reconstitute.
Abstract: Cohesion between sister chromatids, mediated by the chromosomal cohesin complex, is a prerequisite for faithful chromosome segregation in mitosis. Cohesin also has vital roles in DNA repair and transcriptional regulation. The ring-shaped cohesin complex is thought to encircle sister DNA strands, but its molecular mechanism of action is poorly understood and the biochemical reconstitution of cohesin activity in vitro has remained an unattained goal. Here we reconstitute cohesin loading onto DNA using purified fission yeast cohesin and its loader complex, Mis4(Scc2)-Ssl3(Scc4) (Schizosaccharomyces pombe gene names appear throughout with their more commonly known Saccharomyces cerevisiae counterparts added in superscript). Incubation of cohesin with DNA leads to spontaneous topological loading, but this remains inefficient. The loader contacts cohesin at multiple sites around the ring circumference, including the hitherto enigmatic Psc3(Scc3) subunit, and stimulates cohesin's ATPase, resulting in efficient topological loading. The in vitro reconstitution of cohesin loading onto DNA provides mechanistic insight into the initial steps of the establishment of sister chromatid cohesion and other chromosomal processes mediated by cohesin.
280 citations
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TL;DR: Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans, but recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuPLoidy.
Abstract: Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.
2,200 citations
TL;DR: Three chromosmal proteins that prevent premature separation of sister chromatids in yeast are described, two of which are members of the SMC family, which are putative ATPases with coiled-coil domains.
1,545 citations
TL;DR: It is proposed that cohesin functions as a transcriptional insulator, and it is speculated that subtle deficiencies in this function contribute to ‘cohesinopathies’ such as Cornelia de Lange syndrome.
Abstract: Cohesin complexes mediate sister-chromatid cohesion in dividing cells but may also contribute to gene regulation in postmitotic cells. How cohesin regulates gene expression is not known. Here we describe cohesin-binding sites in the human genome and show that most of these are associated with the CCCTC-binding factor (CTCF), a zinc-finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19/IGF2 (insulin-like growth factor 2) locus. This role of cohesin seems to be independent of its role in cohesion. We propose that cohesin functions as a transcriptional insulator, and speculate that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome.
1,164 citations
TL;DR: It is shown that Esp1 causes the dissociation of Scc1 from chromosomes by stimulating its cleavage by proteolysis, and a mutant SCC1 is described that is resistant to Esp1-dependent cleavage and which blocks both sister-chromatid separation and the dissociations from chromosomes.
Abstract: Cohesion between sister chromatids is established during DNA replication and depends on a multiprotein complex called cohesin Attachment of sister kinetochores to the mitotic spindle during mitosis generates forces that would immediately split sister chromatids were it not opposed by cohesion Cohesion is essential for the alignment of chromosomes in metaphase but must be abolished for sister separation to start during anaphase In the budding yeast Saccharomyces cerevisiae, loss of sister-chromatid cohesion depends on a separating protein (separin) called Esp1 and is accompanied by dissociation from the chromosomes of the cohesion subunit Scc1 Here we show that Esp1 causes the dissociation of Scc1 from chromosomes by stimulating its cleavage by proteolysis A mutant Scc1 is described that is resistant to Esp1-dependent cleavage and which blocks both sister-chromatid separation and the dissociation of Scc1 from chromosomes The evolutionary conservation of separins indicates that the proteolytic cleavage of cohesion proteins might be a general mechanism for triggering anaphase
1,021 citations
TL;DR: This extensive proteomic analysis of human nucleoli shows that nucleoli have a surprisingly large protein complexity and supports the view that the nucleolus may perform additional functions beyond its known role in ribosome subunit biogenesis.
989 citations