Elsevier

Experimental Cell Research

Volume 318, Issue 12, 15 July 2012, Pages 1386-1393
Experimental Cell Research

Review Article
Cohesin in determining chromosome architecture

https://doi.org/10.1016/j.yexcr.2012.03.016Get rights and content

Abstract

Cells use ring-like structured protein complexes for various tasks in DNA dynamics. The tripartite cohesin ring is particularly suited to determine chromosome architecture, for it is large and dynamic, may acquire different forms, and is involved in several distinct nuclear processes. This review focuses on cohesin's role in structuring chromosomes during mitotic and meiotic cell divisions and during interphase.

Introduction

Roughly one-fourth of all of our protein-encoding genes code for proteins involved in genome maintenance and cell division, which illustrates the enormous complexity and effort that eukaryotic cells have evolved to divide and faithfully transmit their genomes to the next generation. While many elaborate concepts describing these processes have been formulated and a wealth of information has been accumulated about many fundamental events of cell division, there are still huge gaps in our knowledge concerning, for example, chromosome architecture and dynamics.

Even though condensed metaphase chromosomes are known already to school-kids through their textbooks, the layers of structural organization that are required to assemble and partition these chromosomes remain poorly understood. Heterochromatin versus euchromatin, centromeric versus chromosomal arm organization, intergenic versus genic regions, repetitive versus non-repetitive elements, nucleolar or nuclear-envelope-associated regions and many other chromosomal features define chromosome architecture in space and time. It is therefore not surprising that cells have evolved a sophisticated molecular machinery to manage this complex level of organization.

Among the major chromosome organizers is a ubiquitous family of protein complexes based on structural maintenance of chromosomes (SMC) proteins, whose unique structural features make them particularly suited for handling an extensive polymer such as a chromosomal fiber. This was realized quickly after the first description of SMC proteins in 1993 [1], and SMC proteins were subsequently suggested to function as motor proteins, clamps, or crossties that centrally contribute to chromosome structure [2], [3], [4], [5]. SMC proteins feature two globular domains at the ends of a ~ 45 nm long intra-molecular coiled coil that both serve for SMC protein dimerization (Fig. 1A). Specific pairs of SMC proteins form via a high-affinity interaction between the “hinge” domains at one end of the coil “arms”. At the same time, the ATPase “head” domains at the other end can dynamically associate and dissociate upon binding and hydrolysis of ATP, respectively [6]. A so-called kleisin protein further connects the two head domains to form a closed ring-like structure (Fig. 1B). This large ring architecture seems ideal to clasp chromosomes inter- or intra-molecularly between the SMC arms in order to tie them up.

The principle of entrapping DNA within a ring is certainly not unique to SMC complexes. A number of proteins that manipulate nucleic acids, including for example replicative helicases such as the MCM licensing factors, RNA helicases such as the Rho transcription terminator, or DNA replication processivity factors such as PCNA or the β-subunit of prokaryotic DNA polymerase III form rings with a six-fold symmetry and a central hole large enough to encompass a double helix (Fig. 1A) [7]. Similarly, DNA mismatch repair proteins like MSH2 and MSH6 can form sliding clamps, i.e. rings that, once they hit a mismatched base-pair, may move further and recruit more clamps [8]. A ring architecture is in general well suited whenever protein complexes need to move along DNA, as rings can – in principle – rapidly slide along nucleic acid strands for long distances without falling off. What makes SMC complexes unique is their ring diameter, which is at least an order of magnitude larger than the rings of the aforementioned complexes, allowing SMCs to topologically encircle not only one DNA helix but two DNA helices, which may even be wrapped around nucleosomes. In this brief review, we discuss how a particular SMC complex named cohesin can exploit this mode of action to determine the architecture of chromosomes and draw parallels to the function of the related condensin, SMC5/6, and prokaryotic SMC complexes that are described in other articles of this special issue.

Section snippets

Cohesin holds sister chromatids together

The cohesin complex was first identified in genetic screens that aimed to identify proteins required for holding together sister chromatids [9], [10]. Biochemical and structural studies demonstrated that cohesin's kleisin subunit SCC1 (also named RAD21 or MCD1) simultaneously binds to both head domains of an SMC1/SMC3 heterodimer and to a fourth subunit that is predicted to be largely composed of HEAT-repeat motifs (named SCC3 in yeast and present in two isoforms named SA1 and SA2 in metazoan

Cohesin regulates higher order chromosome structure during mitosis and meiosis

Besides generating sister chromatid cohesion, ring-shaped complexes such as cohesin are well suited to contribute to other aspects of higher order chromosome structure. One may imagine inter-molecular links between two chromosomes in G1 phase, intra-molecular connections between distinct regions on one chromosome, or even linkage of more than two double-stranded DNA molecules through multiple ring interactions. Indeed, there is evidence supporting at least the latter two modes.

In metaphase,

Cohesin organizes the interphase nucleus

Cohesin's architectural function is not limited to mitotic or meiotic chromosomes. There is increasing evidence that cohesin complexes play a central function in gene regulation independent of their role in sister chromatid cohesion. Depletion or mutation of NIPBL or of cohesin subunits was found to have predominant effects on the expression of a number of developmental transcriptional regulators in flies and zebrafish [66], [67], [68], [69], [70]. In humans, the developmental disorder Cornelia

Outlook

In recent years we have seen an amazing expansion of our knowledge on how cohesin shapes chromosomes. Yet, our current insights may only be a glimpse into the real complexity of cohesin-mediated order and dynamics of chromosome architecture in various cell types, distinct organisms, different stages of the cell cycle, and in the multitude of processes cohesin is involved in. In order to understand the molecular machinery behind the multitude of cohesin functions, we need to further take into

Acknowledgments

Work in the authors' laboratories is supported by funding from the German Research Foundation (DFG) Priority Programme 1384.

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