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Losada A.,Chromosome Dynamics Group
Nature Reviews Cancer | Year: 2014

Cohesin is an evolutionarily conserved, four-subunit complex that entraps DNA fibres within its ring-shaped structure. It was originally identified and named for its role in mediating sister chromatid cohesion, which is essential for chromosome segregation and DNA repair. Increasing evidence indicates that cohesin participates in other processes that involve DNA looping, most importantly, transcriptional regulation. Mutations in genes encoding cohesin subunits and other regulators of the complex have recently been identified in several types of tumours. Whether aneuploidy that results from chromosome missegregation is the major contribution of cohesin mutations to cancer progression is under debate. © 2014 Macmillan Publishers Limited.

Remeseiro S.,Chromosome Dynamics Group
Current opinion in cell biology | Year: 2013

Cohesin is a four subunit complex, conserved from yeast to man, with the ability to hold together two DNA segments within its ring-shaped structure. When the two segments belong to sister chromatids, cohesin is mediating cohesion, which is essential for chromosome segregation in mitosis and meiosis and for homologous DNA repair. When the two DNA segments are in the same chromatid, a loop is formed. These chromatin loops are emerging as a mechanism for controlling the communication between enhancers and promoters and thereby regulate gene expression. They also facilitate DNA replication and recombination. Given all its essential functions, it is not surprising that mutations in cohesin and its interacting factors have been associated to cancer and developmental syndromes known as cohesinopathies. Copyright © 2012 Elsevier Ltd. All rights reserved.

Rivera T.,Chromosome Dynamics Group | Rivera T.,Salk Institute for Biological Studies | Ghenoiu C.,Rockefeller University | Ghenoiu C.,The New School | And 4 more authors.
EMBO Journal | Year: 2012

Shugoshins (Sgo) are conserved proteins that act as protectors of centromeric cohesion and as sensors of tension for the machinery that eliminates improper kinetochore-microtubule attachments. Most vertebrates contain two Sgo proteins, but their specific functions are not always clear. Xenopus laevis Sgo1, XSgo1, protects centromeric cohesin from the prophase dissociation pathway. Here, we report the identification of XSgo2 and show that it does not regulate cohesion. Instead, we find that it participates in bipolar spindle assembly. Both Sgo proteins interact physically with the Chromosomal Passenger Complex (CPC) containing Aurora B, a key regulator of mitosis, but the functional consequences of such interaction are distinct. XSgo1 is required for proper localization of the CPC while XSgo2 positively contributes to its activation and the subsequent phosphorylation of at least one key substrate for bipolar spindle assembly, the microtubule depolymerizing kinesin MCAK (Mitotic Centromere-Associated Kinesin). Thus, the two Xenopus Sgo proteins have non-overlapping functions in chromosome segregation. Our results further suggest that this functional specificity could rely on the association of XSgo1 and XSgo2 with different regulatory subunits of the PP2A complex. © 2012 European Molecular Biology Organization.

Remeseiro S.,Chromosome Dynamics Group | Cuadrado A.,Chromosome Dynamics Group | Carretero M.,Chromosome Dynamics Group | Martnez P.,Telomeres and Telomerase Group | And 5 more authors.
EMBO Journal | Year: 2012

Cohesin is a protein complex originally identified for its role in sister chromatid cohesion, although increasing evidence portrays it also as a major organizer of interphase chromatin. Vertebrate cohesin consists of Smc1, Smc3, Rad21/Scc1 and either stromal antigen 1 (SA1) or SA2. To explore the functional specificity of these two versions of cohesin and their relevance for embryonic development and cancer, we generated a mouse model deficient for SA1. Complete ablation of SA1 results in embryonic lethality, while heterozygous animals have shorter lifespan and earlier onset of tumourigenesis. SA1-null mouse embryonic fibroblasts show decreased proliferation and increased aneuploidy as a result of chromosome segregation defects. These defects are not caused by impaired centromeric cohesion, which depends on cohesin-SA2. Instead, they arise from defective telomere replication, which requires cohesion mediated specifically by cohesin-SA1. We propose a novel mechanism for aneuploidy generation that involves impaired telomere replication upon loss of cohesin-SA1, with clear implications in tumourigenesis. © 2012 European Molecular Biology Organization | All Rights Reserved.

Carretero M.,Chromosome Dynamics Group | Remeseiro S.,Chromosome Dynamics Group | Losada A.,Chromosome Dynamics Group
Current Opinion in Cell Biology | Year: 2010

Cohesin was originally identified as a mediator of sister chromatid cohesion both in mitosis and meiosis. Emerging evidences suggest that it also participates in the organization of interphase chromatin. The ring-shaped complex regulates gene expression by constraining chromatin topology in concert with factors such as the insulator CTCF, at least in certain loci. The global relevance of this function of cohesin remains to be assessed, but its contribution to the pathology of the Cornelia de Lange syndrome seems evident. Our current knowledge of the molecular mechanisms underlying cohesin behavior should now be considered from the perspective of its novel functions, which promise to be as relevant for cell viability as cohesion. © 2010 Elsevier Ltd.

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