Cohesin Proteins

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 Cohesin Proteins Background

Eukaryotic cells are faced with a tricky biological problem: they must not only precisely duplicate their chromosomes, but they must also be able to distinguish between identical sister chromatids and ensure that only sisters segregate away from each other towards opposing poles of the spindle. The first clue as to how cells manage this sorting problem came from groundbreaking microscopy studies from Walther Flemming in 1882 where he illustrated pairs of chromatids connected along their entire length. It was not until the advent of mitotic chromosome spreads in 1956, however, that paired sister chromatids could be readily distinguished from homologues, prompting the question as to the molecular nature of this sister chromatid paring. An early candidate for this pairing, known as sister chromatid cohesion, was DNA catenation, which describes the intermolecular intertwining of sister chromatids that result from DNA replication. However, it was noted that catenation between circular minichromosomes is largely resolved in mitosis, suggesting that topological interlinks between sisters was unlikely to mediate cohesion until anaphase onset. Consistent with this, it was later observed that the dissolution of cohesion at the metaphase-to-anaphase transition was dependent on the anaphase-promoting complex/cyclosome (APC/C) protein ubiquitin ligase, indicating that protein components must, at least in part, mediate cohesion between sisters.

Sister chromatid cohesion is important because it ensures that, upon entry into mitosis, each sister chromatid pair bi-orients on the spindle, meaning that one kinetochore attaches to microtubules emanating from one pole and the other sister kinetochore is connected to the opposite pole. Cohesion between bi-oriented sister chromatids is thought to resist the opposing pulling forces of the spindle, creating tension that is sensed by a surveillance mechanism known as the spindle assembly checkpoint (SAC). Accurate bi-orientation of all chromatid pairs signals the termination of the SAC, which in turn promotes anaphase onset via the activation of an ubiquitin ligase known as the anaphase-promoting complex or cyclosome (APC/C). The activated APC/C triggers anaphase by promoting the dissolution of cohesion, which leads to the release of tension between sister chromatids and their subsequent segregation to opposite poles of the spindle. The critical requirement of cohesion in chromosome segregation is highlighted by the fact that failure to tether sister chromatids can lead to incorrect kinetochore-microtubule attachments and prolonged SAC activation, both of which may contribute to aneuploidy and tumourigenesis. In this regard, cohesion dysfunction has been linked to a number of cancers and congenital disorders in humans, further emphasizing the integral role of sister chromatid cohesion in the faithful transmission of the eukaryotic genome.

The Cohesin Complex

Cohesin: Master regulator of sister chromatid cohesion

The discovery of proteinaceous cohesion factors that tether identical sister chromatids from S phase until anaphase revolutionized the understanding of how chromosome segregation is orchestrated during both the mitotic and meiotic cell cycles. While factors required for sister chromatid cohesion were first uncovered from a series of genetic screens in both budding and fission yeasts in the early 1990’s, the identification of additional cohesion proteins was limited by the lack of methods to directly monitor sister chromatid cohesion in vivo. The development of methods to fluorescently tag yeast chromosomal loci, using either fluorescence in situ hybridization (FISH) or an integrated array of operators to which GFP-bound repressors are targeted, permitted the direct visualization of paired and separated sister chromatids by fluorescence microscopy. Application of these microscopy-based approaches, coupled with genetic screening techniques, enabled the discovery of a collection of budding yeast proteins required for sister chromatid cohesion.

Subsequent biochemical and cell biological analyses demonstrated that a subset of these cohesion factors formed the highly conserved multi-subunit complex named cohesin, which consists of four core subunits: the Smc1 and Smc3 ATPases, the Mcd1/Scc1 Į-kleisin and the HEAT repeat-containing protein Scc3/Irr1. While the mechanism of how cohesin tethers sister chromatids remains an item of intense debate, recent studies in both yeast and metazoans reveal that cohesin function is not limited to sister chromatid cohesion, but also plays diverse roles in chromosome metabolism such as mitotic chromosome condensation, higher-order chromatin organization, DNA repair, gene expression, ribosome biogenesis, rDNA stability and centrosome biology. The multiple roles for cohesin in the maintenance of genome integrity is further highlighted by the fact that cohesin dysfunction has been linked to an array of human cancers and developmental syndromes collectively known as cohesinopathies.

The structure and composition of the core cohesin complex. The budding yeast cohesin complex consists of four subunits: the Smc1 and Smc3 ATPases, the Mcd1/Scc1 α-kleisin and the HEAT repeat-containing protein Scc3/Irr1. The core cohesin complex is regulated by a collection of auxiliary proteins, namely Eco1, Pds5 and Wpl1, each of which has unique roles in the modulation of cohesin function. Although the core subunits and regulatory factors of the cohesin complex have been largely conserved throughout evolution, their nomenclature and number of functional homologs varies between species.