Cohesins: chromatin architects in chromosome segregation, control of gene expression and much more

Abstract

Cells have evolved to develop molecules and control mechanisms that guarantee correct chromosome segregation and ensure the proper distribution of genetic material to daughter cells. In this sense, the establishment, maintenance, and removal of sister chromatid cohesion is one of the most fascinating and dangerous processes in the life of a cell because errors in the control of these processes frequently lead to cell death or aneuploidy. The main protagonist in this mechanism is a four-protein complex denominated the cohesin complex. In the last 10 years, we have improved our understanding of the key players in the regulation of sister chromatid cohesion during cell division in mitosis and meiosis. The last 2 years have seen an increase in evidence showing that cohesins have important functions in non-dividing cells, revealing new, unexplored roles for these proteins in the control of gene expression, development, and other essential cell functions in mammals.

Fig. 1

Cohesin subunits and ring-like structure proposed for the cohesin complex. Structural maintenance of chromosomes SMC1 and SMC3 form a heterodimer, interacting through their hinge regions. The SMC1 and SMC3 head domains, which contain the ATPase motifs of these proteins, interact with the C- and N-termini of the SCC1/RAD21 kleisin subunit, respectively, closing the ring. The SCC3/SA/STAG subunit interacts with SCC1/RAD21, contributing to maintenance of the ring structure

Fig. 2

Representation of some factors that contribute to cohesion regulation. a Adherins Scc2/Scc4, also denoted NippedB/Mau-2, form the cohesin loading complex. b The replication fork-associated Eco1/ESCO2 acetyltransferase is required to establish cohesion. c Precocious dissociation of sister (PDS5) and sororin are the best-characterized factors implicated in the maintenance of sister chromatid cohesion

Fig. 3

Chromosome segregation in fly and vertebrate mitosis. In prophase chromosomes, the cohesin complexes are located along the middle region of the arms and at the inner centromere domain. During the prophase/metaphase transition, the kinases Aurora-B and/or Polo-like kinase 1 (PLK1) phosphorylate the SA2 subunit of most cohesin complexes at the arms and promote their removal from chromosomes. Wing apart-like (WAPL) is a regulator of sister chromatid resolution in the mitotic prophase. Centromere cohesins are protected from phosphorylation by phosphatase PP2A, which is recruited to the centromere by shugoshin. Once all chromosomes are bi-oriented at the metaphase plate in the metaphase/anaphase transition, shugoshin and PP2A are delocalized from the centromeres. At this time, the APC/CDC20 complex ubiquitinizes the separase inhibitor securin, which is dissociated from separase, allowing cleavage of the few remaining cohesin complexes at the arms and centromere cohesins

Fig. 4

Chromosome segregation in meiosis. In metaphase I bivalents, cohesin complexes are located at the interchromatid domain along the arms and at the inner centromere domain below the closely associated sister kinetochores. At the onset of anaphase I, only the cohesin complexes at the arms are cleaved by separase to allow segregation of recombined homologues to opposite poles. Centromere cohesins are protected by SGO/PP2A. In metaphase II chromosomes, sister kinetochores attach to microtubules from opposite poles, and cohesin complexes are found at the inner centromere domain. In late prometaphase II chromosomes in mammals, the interaction of microtubules from opposite poles with sister kinetochores generates tension across the centromere and triggers the redistribution of SGO2 and probably PP2A delocalization from centromeres. During the metaphase II/anaphase II transition, separase is now able to cleave remaining centromeric cohesin complexes to trigger chromatid segregation. The chromosomes depicted are telocentric

Fig. 5

Representation of putative models by which cohesins may regulate transcription. a Chromosome-bound cohesin complexes block the transcriptional activation signals from a distal enhancer element, repressing gene expression. b Dissociation of cohesin complexes from chromatin allows the transmission of positive signals from distal elements, activating transcription. c Isolated cohesin subunits may act as transcriptional co-activators by interacting with the transcription initiation complex or with other co-activators