Communication between distinct subunit interfaces of the cohesin complex promotes its topological entrapment of DNA

Guacci, Vincent; Chatterjee, Fiona; Robison, Brett; Koshland, Douglas

doi:10.7554/elife.46347

Cited by 12 publications

(26 citation statements)

References 57 publications

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“…We depleted Pds5p from mitotically arrested cells ( Figure 6—figure supplement 1A ) and examined cohesin binding to chromosomes and loop formation. As published previously, Pds5p depletion caused a marked loss of cohesin all along the chromosome arms from visual inspection ( Figure 6E , first column and 6G, first panel) ( Guacci et al, 2019 ). Concomitantly with the loss of cohesin, the positioned loops disappeared from the chromosome arms genome-wide ( Figure 6E first column, 6F, and Figure 6—figure supplement 1F ).…”

Section: Resultssupporting

confidence: 82%

Cohesin residency determines chromatin loop patterns

Costantino

Lamothe

et al. 2020

eLife

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The organization of chromatin into higher order structures is essential for chromosome segregation, the repair of DNA-damage, and the regulation of gene expression. Using Micro-C XL to detect chromosomal interactions, we observed the pervasive presence of cohesin-dependent loops with defined positions throughout the genome of budding yeast, as seen in mammalian cells. In early S phase, cohesin stably binds to cohesin associated regions (CARs) genome-wide. Subsequently, positioned loops accumulate with CARs at the bases of the loops. Cohesin regulators Wpl1 and Pds5 alter the levels and distribution of cohesin at CARs, changing the pattern of positioned loops. From these observations, we propose that cohesin with loop extrusion activity is stopped by preexisting CAR-bound cohesins, generating positioned loops. The patterns of loops observed in a population of wild-type and mutant cells can be explained by this mechanism, coupled with a heterogeneous residency of cohesin at CARs in individual cells.

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Section: Resultssupporting

confidence: 82%

Cohesin residency determines chromatin loop patterns

Costantino

Lamothe

et al. 2020

eLife

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“…The Smc3-kleisin fusion in itself will not block the operation of the kleisin Ngate or subsequent DNA passage through the head gate. Indeed, a functional kleisin N-gate remains required for the viability of the fusion strains (Guacci et al, 2019).…”

Section: The Dna Trajectory Into the Cohesin Ringmentioning

confidence: 99%

A Structure-Based Mechanism for DNA Entry into the Cohesin Ring

Higashi

Eickhoff²,

Simões³

et al. 2020

Preprint

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Despite key roles in sister chromatid cohesion and chromosome organization, the mechanism by which cohesin rings are loaded onto DNA is still unknown. Here, we combine biophysical approaches and cryo-EM to visualize a cohesin loading intermediate in which DNA is locked between two gates that lead into the cohesin ring.Building on this structural framework, we design biochemical experiments to establish the order of events during cohesin loading. In an initial step, DNA traverses an Nterminal kleisin gate that is first opened upon ATP binding and then closed as the cohesin loader locks the DNA against a shut ATPase gate. ATP hydrolysis leads to ATPase gate opening to complete DNA entry. Whether DNA loading is successful, or rather results in loop extrusion, might be dictated by a conserved kleisin N-terminal tail that guides the DNA through the kleisin gate. Our results establish the molecular basis for cohesin loading onto DNA.

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“…The Arg65 is located within the RAS21-SMC3 domain in the close proximity of Tyr67, and altering the kinase/ phosphatase recognition motif Arg-X-Tyr around Tyr67 may affect the phosphorylation-based regulation of RAD21 (Amanchy et al 2011;Hoque and Ishikawa 2001;Hornbeck et al 2015;Li et al 2009). In addition, a contact between the PDS5 protein and the RAD21-SMC3/SMC3-head complex is involved in the topological entrapment of DNA by cohesin (Guacci et al 2019). As Arg65 is located towards the solvent, Arg65Gln may impact the RAD21-PDS5 recognition and, thus, disturb their interaction.…”

Section: Rad21 Missense Variants and Their Predicted Effect On Proteimentioning

confidence: 99%

“…The interaction between RAD21 and STAG1/2 is crucial for the proper functioning of the cohesin complex (Guacci et al 2019), and both impairing (Ser345Pro) or over-stabilizing (Pro367Arg) variants within the RAD21-STAG domain are predicted to cause dysfunction of the complex, presumably through affecting the continuous cycle of formation and disengagement of the cohesin ring (Marcos-Alcalde et al 2017).…”

Section: Rad21 Missense Variants and Their Predicted Effect On Proteimentioning

confidence: 99%

“…For two additional variants that could not be modeled, the literature supports that they are likely pathogenic. Phe6 is found close to Ser9, a phosphorylation site described in the human proteome (Gauci et al 2009;Guacci et al 2019). The Phe6Val variant (reported as aVUS) would modify the kinase/phosphatase recognition motif, thus affecting the protein behavior.…”

Section: Rad21 Missense Variants and Their Predicted Effect On Proteimentioning

confidence: 99%

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Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

et al. 2020

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RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.Zeynep Tümer and Raoul C. Hennekam contributed equally.

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Communication between distinct subunit interfaces of the cohesin complex promotes its topological entrapment of DNA

Cited by 12 publications

References 57 publications

Cohesin residency determines chromatin loop patterns

Cohesin residency determines chromatin loop patterns

A Structure-Based Mechanism for DNA Entry into the Cohesin Ring

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

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