Structural Basis and IP6 Requirement for Pds5-Dependent Cohesin Dynamics

Ouyang, Zhuqing; Ge, Zheng; Tomchick, Diana R.; Luo, Xuelian; Yu, Hongtao

doi:10.1016/j.molcel.2016.02.033

Cited by 111 publications

(177 citation statements)

References 46 publications

(85 reference statements)

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“…Scc2 consists almost entirely of helical repeats that fold into a molecular hook. The overall structure of Scc2 is similar to two other Scc1-binding HEAT repeat proteins, Scc3 and Pds5, which also adopt highly bent structures (8,9,27,35,36). Like Scc3 and Pds5, Scc2 interacts with Scc1.…”

mentioning

confidence: 77%

“…In vertebrates, Smc3 acetylation enables the binding of sororin to cohesin and Pds5 (26). Sororin alters the molecular interactions among cohesin, Pds5, and Wapl, and inhibits the releasing activity of the Pds5-Wapl complex (26,27).Mutations of cohesin subunits and accessory proteins cause human developmental diseases termed cohesinopathy, including Cornelia de Lange syndrome (CdLS) (28,29). About 60% of CdLS cases involve mutations of Scc2 [also called Nipped B-like protein (NIPBL)] (30-32).…”

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confidence: 99%

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confidence: 99%

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Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

Kikuchi

Borek

Otwinowski

et al. 2016

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

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The ring-shaped cohesin complex topologically entraps chromosomes and regulates chromosome segregation, transcription, and DNA repair. The cohesin core consists of the structural maintenance of chromosomes 1 and 3 (Smc1-Smc3) heterodimeric ATPase, the kleisin subunit sister chromatid cohesion 1 (Scc1) that links the two ATPase heads, and the Scc1-bound adaptor protein Scc3. The sister chromatid cohesion 2 and 4 (Scc2-Scc4) complex loads cohesin onto chromosomes. Mutations of cohesin and its regulators, including Scc2, cause human developmental diseases termed cohesinopathy. Here, we report the crystal structure of Chaetomium thermophilum (Ct) Scc2 and examine its interaction with cohesin. Similar to Scc3 and another Scc1-interacting cohesin regulator, precocious dissociation of sisters 5 (Pds5), Scc2 consists mostly of helical repeats that fold into a hook-shaped structure. Scc2 binds to Scc1 through an N-terminal region of Scc1 that overlaps with its Pds5-binding region. Many cohesinopathy mutations target conserved residues in Scc2 and diminish Ct Scc2 binding to Ct Scc1. Pds5 binding to Scc1 weakens the Scc2-Scc1 interaction. Our study defines a functionally important interaction between the kleisin subunit of cohesin and the hook of Scc2. Through competing with Scc2 for Scc1 binding, Pds5 might contribute to the release of Scc2 from loaded cohesin, freeing Scc2 for additional rounds of loading.transcription | cohesinopathy | X-ray crystallography | cohesin loading | HEAT repeat C ohesin consists of four core subunits: structural maintenance of chromosomes 1 and 3 (Smc1 and Smc3), and sister chromatid cohesion 1 and 3 (Scc1 and Scc3). (1-5). Smc1 and Smc3 are related ATPases that heterodimerize through their hinge domains. The C-terminal winged helix domain and the N-terminal helical domain (NHD) of Scc1 bind to the Smc1 ATPase head and a coiled-coil segment adjacent to the Smc3 ATPase head, respectively, forming a tripartite ring (6, 7). Scc3 contains Huntingtin-elongation factor 3-protein phosphatase 2A-TOR1 (HEAT) repeats, binds to the middle region of Scc1, and provides a landing pad for several cohesin regulators (8, 9). Cohesin can topologically trap DNA inside its ring (10), thereby regulating many facets of chromosome biology. During interphase, cohesin mediates the formation of chromosome loops that impact transcription (11). During S phase, cohesin physically links replicated chromosomes to establish sister-chromatid cohesion (12, 13), which is a prerequisite for faithful chromosome segregation during mitosis. Finally, cohesin contributes to homologydirected repair of DNA breaks, in part, through holding the sister chromatid in proximity of the breaks and presenting it as the repair template (14).For cohesin to accomplish these diverse tasks, its association with chromosomes has to be tightly controlled both spatially and temporally. Cohesin dynamics on chromosomes are regulated by a set of accessory proteins, including the Scc2-Scc4 loading complex and the releasing complex comprising Pds5 and wing...

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confidence: 77%

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confidence: 99%

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Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

Kikuchi

Borek

Otwinowski

et al. 2016

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

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111

116

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“…Subsequent ATP rebinding, with the aid of Wapl and Pds5, triggers Psm3 Smc3 -Rad21 Scc1 opening, resulting in DNA release. Ouyung et al have shown that Pds5 interacts with Scc1’s N-terminal domain which includes the Smc3 binding interface; by occupying this interface, Pds5 physically prevents Scc1 binding to Smc3 [40]. These results suggest that Wapl initially destabilizes the Smc3-Scc1 interaction and Pds5 then keeps the DNA transport gate open.…”

Section: Topological Dna Binding By Cohesinmentioning

confidence: 99%

“…These results suggest that Wapl initially destabilizes the Smc3-Scc1 interaction and Pds5 then keeps the DNA transport gate open. Crystallographic and bioinformatic studies have shown that Pds5 and Scc2, as well as Scc3, are paralogs and share similar U-shaped structures that are composed of stacked HEAT repeat helices [27–29,40]. Both Pds5 and Scc2 interact with the flexible middle domain of Scc1.…”

Section: Topological Dna Binding By Cohesinmentioning

confidence: 99%

DNA entry, exit and second DNA capture by cohesin: insights from biochemical experiments

Murayama

2018

Nucleus

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Cohesin is a ring-shaped, multi-subunit ATPase assembly that is fundamental to the spatiotemporal organization of chromosomes. The ring establishes a variety of chromosomal structures including sister chromatid cohesion and chromatin loops. At the core of the ring is a pair of highly conserved SMC (Structural Maintenance of Chromosomes) proteins, which are closed by the flexible kleisin subunit. In common with other essential SMC complexes including condensin and the SMC5-6 complex, cohesin encircles DNA inside its cavity, with the aid of HEAT (Huntingtin, elongation factor 3, protein phosphatase 2A and TOR) repeat auxiliary proteins. Through this topological embrace, cohesin is thought to establish a series of intra- and interchromosomal interactions by tethering more than one DNA molecule. Recent progress in biochemical reconstitution of cohesin provides molecular insights into how this ring complex topologically binds and mediates DNA-DNA interactions. Here, I review these studies and discuss how cohesin mediates such chromosome interactions.

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Releasing the cohesin ring: A rigid scaffold model for opening the DNA exit gate by Pds5 and Wapl

Ouyang

2017

BioEssays

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The ring-shaped ATPase machine, cohesin, regulates sister chromatid cohesion, transcription, and DNA repair by topologically entrapping DNA. Here, we propose a rigid scaffold model to explain how the cohesin regulators Pds5 and Wapl release cohesin from chromosomes. Recent studies have established the Smc3-Scc1 interface as the DNA exit gate of cohesin, revealed a requirement for ATP hydrolysis in ring opening, suggested regulation of the cohesin ATPase activity by DNA and Smc3 acetylation, and provided insights into how Pds5 and Wapl open this exit gate. We hypothesize that Pds5, Wapl, and SA1/2 form a rigid scaffold that docks on Scc1 and anchors the N-terminal domain of Scc1 (Scc1N) to the Smc1 ATPase head. Relative movements between the Smc1-3 ATPase heads driven by ATP and Wapl disrupt the Smc3-Scc1 interface. Pds5 binds the dissociated Scc1N and prolongs this open state of cohesin, releasing DNA. We review the evidence supporting this model and suggest experiments that can further test its key principles.

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Structural Basis and IP6 Requirement for Pds5-Dependent Cohesin Dynamics

Cited by 111 publications

References 46 publications

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

DNA entry, exit and second DNA capture by cohesin: insights from biochemical experiments

Releasing the cohesin ring: A rigid scaffold model for opening the DNA exit gate by Pds5 and Wapl

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