Cohesinopathy mutations disrupt the subnuclear organization of chromatin

Gard, Scarlett; Light, William H.; Xiong, Bo; Bose, Tania; McNairn, Adrian J.; Harris, Bethany; Fleharty, Brian; Seidel, Chris; Brickner, Jason H.; Gerton, Jennifer L.

doi:10.1083/jcb.20090607520091116c

Cited by 19 publications

(24 citation statements)

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“…Key roles for cohesin have been shown in a number of cellular processes including DNA repair, 21,22 chromatin modification, 23 DNA condensation 24 and transcriptional regulation in Drosophila, [25][26][27][28] [36][37][38] have demonstrated that the function of Scc2/NIPBL in sister chromatid cohesion is spatially and temporally associated with that of Scc4/MAU2. The C. elegans homolog mau-2 was originally identified for its role in axon guidance 39 and has subsequently been show to have a role in mitotic chromosome segregation.…”

Section: Cdlsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIPBL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIPBL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.

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Section: Cdlsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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“…2A) (also see ref. 33), nor did it affect cohesion of a circular, CEN/ ARS minichromosome (Fig. S3A).…”

Section: Resultsmentioning

confidence: 99%

Binding, sliding, and function of cohesin during transcriptional activation

Borrie

Campor

Joshi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The ring-shaped cohesin complex orchestrates long-range DNA interactions to mediate sister chromatid cohesion and other aspects of chromosome structure and function. In the yeast Saccharomyces cerevisiae, the complex binds discrete sites along chromosomes, including positions within and around genes. Transcriptional activity redistributes the complex to the 3′ ends of convergently oriented gene pairs. Despite the wealth of information about where cohesin binds, little is known about cohesion at individual chromosomal binding sites and how transcription affects cohesion when cohesin complexes redistribute. In this study, we generated extrachromosomal DNA circles to study cohesion in response to transcriptional induction of a model gene, URA3. Functional cohesin complexes loaded onto the locus via a poly(dA:dT) tract in the gene promoter and mediated cohesion before induction. Upon transcription, the fate of these complexes depended on whether the DNA was circular or not. When gene activation occurred before DNA circularization, cohesion was lost. When activation occurred after DNA circularization, cohesion persisted. The presence of a convergently oriented gene also prevented transcription-driven loss of functional cohesin complexes, at least in M phase-arrested cells. The results are consistent with cohesin binding chromatin in a topological embrace and with transcription mobilizing functional complexes by sliding them along DNA.T he protein complex known as cohesin organizes eukaryotic genomes into structures that segregate faithfully between dividing cells. The complex was first discovered for its role in mediating sister chromatid cohesion, but it is now known to participate in numerous aspects of chromosome biology (1, 2). Cohesin is clinically relevant because mutations in subunits of the complex or in factors that load and activate the complex lead to developmental disorders such as Cornelia de Lange syndrome, Roberts syndrome, and Warsaw breakage syndrome (3, 4).Cohesin is a ring-shaped complex composed of four subunits named Smc1, Smc3, Scc3, and Mcd1/Scc1 in budding yeast. The complex is thought to embrace DNA topologically with chromatin fibers passing through a central open channel (5-7). A substantial body of work supports a model in which cohesion arises from single cohesin complexes that embrace both sister chromatids [the double embrace model (6)]. Whether the central channel is large enough to accommodate both chromatids has recently been brought into question (8). In addition, the behavior of cohesin has not always been consistent with a double embrace by single complexes (for examples, see refs. 9-11). These situations usually involve a perturbation that causes loss of cohesion but not a loss of cohesin binding from chromatin. Such results force consideration of alternative models in which cohesin complexes embrace only one chromatid topologically and interact with other cohesin complexes or chromatin features to mediate cohesion (9,11,12).Cohesin binds densely in centromeric regions of chromos...

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“…For example, hypotonic lysis of cohesin-depleted cells show chromatin loops that appear to be larger than in control cells, consistent with a change in the spacing of replication origins discussed above [56]. When introduced into budding yeast, human cohesin molecules isolated from patients with cohesin mutations cause the dispersal of normally clustered tRNA genes and alter the nuclear position and the activity of specific genes [72]. Elegant experiments from the lab of Jan-Michael Peters show that the loss of Wapl from non-dividing cells reduces cohesin turnover, increases the association of cohesin with chromatin, and dramatically alters the organisation of interphase chromatin (J-M Peters, personal communication).…”

Section: Cohesin Shapes Interphase Chromatin By Forming Long-range Inmentioning

confidence: 64%

Section: Cohesin Shapes Interphase Chromatin By Forming Long-range Inmentioning

confidence: 66%

Cohesin and chromatin organisation

Seitan

Merkenschlager

2012

Current Opinion in Genetics & Development

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Cohesinopathy mutations disrupt the subnuclear organization of chromatin

Cited by 19 publications

References 0 publications

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

Binding, sliding, and function of cohesin during transcriptional activation

Cohesin and chromatin organisation

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