Review ArticleCohesin in determining chromosome architecture
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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Cited by (32)
Three-Dimensional Genomic Structure and Cohesin Occupancy Correlate with Transcriptional Activity during Spermatogenesis
2019, Cell ReportsCitation Excerpt :The increased labeling intensity at the axis suggests that RAD21L has an important X chromosome scaffolding function, but the reduced number of peaks (compared to the autosomes) indicates that the detected peaks correspond to cohesins that do not interact directly with DNA at the axis. In fact, REC8 and RAD21L bind to both head domains of a structural maintenance of chromosome (SMC) heterodimer, forming a ring-like protein structure topologically encircling sister chromatids to the SC, a core axis from which chromatin loops emerge (Haering and Jessberger, 2012). This structure could block REC8 and RAD21L access to chromatin, preventing detection at the axis by ChIP-seq.
Expression of Epitope-Tagged SYN3 Cohesin Proteins Can Disrupt Meiosis in Arabidopsis
2014, Journal of Genetics and GenomicsCitation Excerpt :Sister chromatid cohesion complexes play critical roles in a number of cellular processes, including the proper segregation of chromosomes during mitosis and meiosis, chromosome condensation, DNA double strand break repair, and the regulation of gene expression (reviewed in Haering and Jessberger, 2012; Peters, 2012; Seitan and Merkenschlager, 2012; Rudra and Skibbens, 2013).
Centromere tethering confines chromosome domains
2013, Molecular CellCitation Excerpt :A major source of chromatin organization is the structural maintenance of chromosomes protein complex cohesin. While the role of cohesin in holding sister chromatids together in mitosis is well established, it is becoming increasingly evident that cohesin also serves a vital role in interphase chromatin gene regulation through looping (as reviewed in Haering and Jessberger, 2012; Seitan and Merkenschlager, 2012; and Sofueva and Hadjur, 2012). Given the regulatory role for cohesin looping, we predict a role for cohesin in the organization of chromatin into territories and maintaining chromatin dynamics during interphase.
Cohesin in Gametogenesis
2013, Current Topics in Developmental BiologyCitation Excerpt :Thus, increasing attention should be given to the role of cohesin-regulatory factors in meiosis. Several factors interact with cohesins and regulate their various functions in somatic cells (Fig. 1.1A; reviewed in Haering & Jessberger, 2012; Merkenschlager, 2010; Nasmyth, 2011; Nasmyth & Haering, 2009; Wood et al., 2010). Here, we briefly discuss these factors and their roles in the mitotic cell cycle and discuss in more detail the current state of knowledge of their expression and functions in germ cells.