Cohesin in development and disease

Remeseiro, Silvia; Cuadrado, Ana; Losada, Ana

doi:10.1242/dev.090605

Cited by 81 publications

(70 citation statements)

References 53 publications

(37 reference statements)

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“…Thus, proper levels of Scc2 are particularly important for human development. Because the cells of patients with CdLS have no gross defects in cohesin loading or sister-chromatid cohesion, the prevailing model is that Scc2 mutations cause cohesinopathy by perturbing the transcription of developmental genes (28,29). Although it is possible that low levels of Scc2 impair cohesin loading at specific genes, it is equally possible that the cohesin-Scc2 complex is the functional entity that regulates transcription.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

“…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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Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

Kikuchi

Borek

Otwinowski

et al. 2016

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

113

125

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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.

113

125

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“…This looping can be mediated in part by the cohesin complex (Dorsett, 2011;Remeseiro et al, 2013). Chromatin immunoprecipitation followed by sequencing (ChIP-seq) and biochemical analyses revealed that Mediator collaborates with the cohesin complex to link enhancers to core promoters to activate transcription of different sets of genes in mouse embryonic stem cells (ESCs) and mouse embryonic fibroblasts (MEFs) (Kagey et al, 2010).…”

Section: Interactions With Master Regulators Of Cell Fatementioning

confidence: 99%

The Mediator complex: a master coordinator of transcription and cell lineage development

2014

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Mediator is a multiprotein complex that is required for gene transcription by RNA polymerase II. Multiple subunits of the complex show specificity in relaying information from signals and transcription factors to the RNA polymerase II machinery, thus enabling control of the expression of specific genes. Recent studies have also provided novel mechanistic insights into the roles of Mediator in epigenetic regulation, transcriptional elongation, termination, mRNA processing, noncoding RNA activation and super enhancer formation. Based on these specific roles in gene regulation, Mediator has emerged as a master coordinator of development and cell lineage determination. Here, we describe the most recent advances in understanding the mechanisms of Mediator function, with an emphasis on its role during development and disease. KEY WORDS: Mediator complex, Transcription, Cell fate, Lineage development, Disease IntroductionMediator is a large, multisubunit complex that was discovered following efforts to understand how RNA polymerase II (Pol II)-mediated transcription is regulated by transcription factors in yeast (Nonet and Young, 1989;Kelleher et al., 1990;Thompson et al., 1993;Kim et al., 1994). The complex, which consists of ~30 polypeptides ( Fig. 1), shows conservation from yeast to humans and plays an indispensable role in regulating transcription. Multiple laboratories then used a variety of procedures to isolate mammalian Mediator complexes, which were named TRAP/SMCC, NAT, ARC, DRIP, Srb/MED, PC2, CRSP and mouse Mediator (Jiang et al., 1998;Sun et al., 1998; Boyer et al., 1999;Ito et al., 1999;Kingston, 1999;Näär et al., 1999;Rachez et al., 1999;Ryu et al., 1999;Malik et al., 2000). In 2004, a unified nomenclature for Mediator was established, consisting of MED1 to MED31, together with the cyclin-dependent kinase (CDK) 8-cyclin C pair and several paralogs such as MED1-like (MED1L), MED12L, MED13L and CDK19 (Bourbon et al., 2004). The Mediator complex can be divided into four distinct modules termed the head, middle, tail and CDK8 kinase module, which contains CDK8 (or its paralog CDK19), cyclin C, MED12 (or MED12L) and MED13 (or MED13L) subunits (Malik and Roeder, 2010;Taatjes, 2010). Importantly, the subunit composition of Mediator can vary and is not restricted to a single isoform. For example, immunodepletion of the Mediator complex from HeLa nuclear extracts with an anti-CDK8 antibody revealed that Mediator exists as at least two main isoforms, distinguished by the presence or absence of the CDK8 submodule (Wang et al., 2001). In addition, MED1 and MED26 are not present in all isolated isoforms (Malik and Roeder, 2010).After the initial discovery of Mediator, research mainly focused on how the Mediator complex conveys signals from transcription factors to the Pol II machinery and general transcription factors (GTFs). These studies led to the formulation of the 'bridge' model, in which Mediator connects the transcription factor and Pol II machineries and promotes formation of the pre-initiation compl...

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“…Cohesin's canonical function establishes cohesion between replicated sister chromatids, thus ensuring their precise segregation at anaphase (1,2). Research over the last one and a half decades has revealed that cohesin has additional cohesion-independent functions in interphase nuclei, such as chromatin organization and transcription regulation (3,4).…”

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confidence: 99%

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

Dasgupta

Antony

Braithwaite

et al. 2016

Journal of Biological Chemistry

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Cohesin, a multi-subunit protein complex involved in chromosome organization, is frequently mutated or aberrantly expressed in cancer. Multiple functions of cohesin, including cell division and gene expression, highlight its potential as a novel therapeutic target. The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes. Following anaphase, ac-SMC3 is deacetylated by HDAC8. Reversal of SMC3 acetylation is imperative for recycling cohesin so that it can be reloaded in interphase for both non-mitotic and mitotic functions. We blocked deacetylation of ac-SMC3 using an HDAC8-specific inhibitor PCI-34051 in MCF7 breast cancer cells, and examined the effects on transcription of cohesin-dependent genes that respond to estrogen. HDAC8 inhibition led to accumulation of ac-SMC3 as expected, but surprisingly, had no influence on the transcription of estrogen-responsive genes that are altered by siRNA targeting of RAD21 or SMC3. Knockdown of RAD21 altered estrogen receptor ␣ (ER) recruitment at SOX4 and IL20, and affected transcription of these genes, while HDAC8 inhibition did not. Rather, inhibition of HDAC8 delayed cell cycle progression, suppressed proliferation and induced apoptosis in a concentration-dependent manner. We conclude that HDAC8 inhibition does not change the estrogen-specific transcriptional role of cohesin in MCF7 cells, but instead, compromises cell cycle progression and cell survival. Our results argue that candidate inhibitors of cohesin function may differ in their effects depending on the cellular genotype and should be thoroughly tested for predicted effects on cohesin's mechanistic roles.The cohesin complex is a chromatin-associated multi-subunit protein comprised of two SMC (structural maintenance of chromosomes, SMC1A and SMC3) 2 and two non-SMC subunits (RAD21, STAG1/2). Cohesin's canonical function establishes cohesion between replicated sister chromatids, thus ensuring their precise segregation at anaphase (1, 2). Research over the last one and a half decades has revealed that cohesin has additional cohesion-independent functions in interphase nuclei, such as chromatin organization and transcription regulation (3, 4).Recently, cancer genome sequencing projects have revealed that genes encoding cohesin subunits are frequently mutated in several different types of cancer, with particularly high frequency in acute myeloid leukemia (AML) (5-9). Recent mouse models indicate that cohesin contributes to leukemia progression likely through controlling transcription and genome organization, rather than through chromosome separation (10 -12). In breast cancer, the cohesin subunit RAD21 is overexpressed and confers poor prognosis (13,14). We previously showed that cohesin mediates transcription of the MYC gene (15-17) and modulates the transcription of estrogen-dependent genes in MCF7 breast cancer cells (18). The emergence of cohesin as an important contributor to cancer has generated interest in the development of therapeutics that compromise ...

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Cohesin in development and disease

Cited by 81 publications

References 53 publications

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy

The Mediator complex: a master coordinator of transcription and cell lineage development

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

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