Releasing Activity Disengages Cohesin’s Smc3/Scc1 Interface in a Process Blocked by Acetylation

Beckouët, Frederick; Srinivasan, Manoj; Roig, Maurici B.; Chan, Kok-Lung; Scheinost, Johanna C.; Batty, Paul; Hu, Bin; Petela, Naomi J; Gligoris, Thomas G.; Smith, Alexandra C.; Strmecki, Lana; Rowland, Benjamin D.; Nasmyth, Kim

doi:10.1016/j.molcel.2016.01.026

Cited by 116 publications

(180 citation statements)

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“…SMC3 undergoes a cycle of deacetylation and acetylation, which is essential for cohesin functions (Beckouet et al 2010). Although the impact of SMC3 hyperacetylation on mitosis and cell cycle progression remains to be fully elucidated, recent studies suggest that hyperacetylation inhibits sister chromatid release at anaphase (Beckouet et al 2016; Gligoris et al 2014). Since TH34 treatment induces hyperacetylation of SMC3 in high-grade neuroblastoma cells by blocking HDAC8 (Fig.…”

Section: Resultsmentioning

confidence: 99%

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

et al. 2018

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High histone deacetylase (HDAC) 8 and HDAC10 expression levels have been identified as predictors of exceptionally poor outcomes in neuroblastoma, the most common extracranial solid tumor in childhood. HDAC8 inhibition synergizes with retinoic acid treatment to induce neuroblast maturation in vitro and to inhibit neuroblastoma xenograft growth in vivo. HDAC10 inhibition increases intracellular accumulation of chemotherapeutics through interference with lysosomal homeostasis, ultimately leading to cell death in cultured neuroblastoma cells. So far, no HDAC inhibitor covering HDAC8 and HDAC10 at micromolar concentrations without inhibiting HDACs 1, 2 and 3 has been described. Here, we introduce TH34 (3-(N-benzylamino)-4-methylbenzhydroxamic acid), a novel HDAC6/8/10 inhibitor for neuroblastoma therapy. TH34 is well-tolerated by non-transformed human skin fibroblasts at concentrations up to 25 µM and modestly impairs colony growth in medulloblastoma cell lines, but specifically induces caspase-dependent programmed cell death in a concentration-dependent manner in several human neuroblastoma cell lines. In addition to the induction of DNA double-strand breaks, HDAC6/8/10 inhibition also leads to mitotic aberrations and cell-cycle arrest. Neuroblastoma cells display elevated levels of neuronal differentiation markers, mirrored by formation of neurite-like outgrowths under maintained TH34 treatment. Eventually, after long-term treatment, all neuroblastoma cells undergo cell death. The combination of TH34 with plasma-achievable concentrations of retinoic acid, a drug applied in neuroblastoma therapy, synergistically inhibits colony growth (combination index (CI) < 0.1 for 10 µM of each). In summary, our study supports using selective HDAC inhibitors as targeted antineoplastic agents and underlines the therapeutic potential of selective HDAC6/8/10 inhibition in high-grade neuroblastoma.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2234-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

et al. 2018

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“…More is known about the mechanism of release. Cohesin dissociates from chromosomes after cleavage of Scc1 by separase at the onset of anaphase (Uhlmann et al, 1999) but at other stages of the cycle in a manner involving dissociation of the Smc3/Scc1 interface (Beckouë t et al, 2016). This separase-independent releasing activity depends on a protein called Wapl (Kueng et al, 2006) that binds to a pair of hookshaped proteins, associated with Scc1, namely, Scc3 and Pds5.…”

Section: Introductionmentioning

confidence: 99%

“…This separase-independent releasing activity depends on a protein called Wapl (Kueng et al, 2006) that binds to a pair of hookshaped proteins, associated with Scc1, namely, Scc3 and Pds5. Release also depends on a pair of highly conserved lysine residues (K112 and K113) on Smc3's ATPase, whose modification by the acetyl transferase Eco1 during S phase abolishes release (Beckouë t et al, 2016;Unal et al, 2008), thereby helping to maintain cohesion until the onset of anaphase.…”

Section: Introductionmentioning

confidence: 99%

Deformation mechanisms in a metastable beta titanium twinning induced plasticity alloy with high yield strength and high strain hardening rate

et al. 2018

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SUMMARYAs predicted by the notion that sister chromatid cohesion is mediated by entrapment of sister DNAs inside cohesin rings, there is perfect correlation between co-entrapment of circular minichromosomes and sister chromatid cohesion. In most cells where cohesin loads without conferring cohesion, it does so by entrapment of individual DNAs. However, cohesin with a hinge domain whose positively charged lumen is neutralized loads and moves along chromatin despite failing to entrap DNAs. Thus, cohesin engages chromatin in non-topological, as well as topological, manners. Since hinge mutations, but not Smc-kleisin fusions, abolish entrapment, DNAs may enter cohesin rings through hinge opening. Mutation of three highly conserved lysine residues inside the Smc1 moiety of Smc1/3 hinges abolishes all loading without affecting cohesin's recruitment to CEN loading sites or its ability to hydrolyze ATP. We suggest that loading and translocation are mediated by conformational changes in cohesin's hinge driven by cycles of ATP hydrolysis.

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“…Scc2-Scc4 promotes the loading of cohesin onto chromosomes in telophase and G1 (15). Pds5-Wapl can release cohesin from chromosomes by opening the Smc3-Scc1 interface (6,7,16,17). Both cohesin loading and release by these complexes require the ATPase activity of cohesin (17)(18)(19)(20)(21).…”

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confidence: 99%

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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Releasing Activity Disengages Cohesin’s Smc3/Scc1 Interface in a Process Blocked by Acetylation

Cited by 116 publications

References 40 publications

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

Deformation mechanisms in a metastable beta titanium twinning induced plasticity alloy with high yield strength and high strain hardening rate

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

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