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The maintenance of chromosome structure: positioning and functioning of SMC complexes

Key Points

  • The eukaryotic structural maintenance of chromosomes (SMC) complexes cohesin, condensin and the SMC5/6 complex organize chromosome structure through their association with DNA and influence a large variety of DNA-based processes. These include sister chromatid cohesion, chromosome condensation, transcription and replication.

  • In vivo and in vitro analyses suggest that SMC complexes function by acting as DNA-linking molecules.

  • Cohesin acts intermolecularly to create sister chromatid cohesion, but is thought to create intramolecular links to control transcription. Condensin only displays intramolecular activities that are thought to be essential for its role in chromosome condensation and gene silencing.

  • The role of the SMC5/6 complex in undamaged cells is less clear, but it influences the functions of cohesin and condensin in both direct and indirect ways.

  • Analysis of chromosome–protein interactions by chromatin immunoprecipitation (ChIP) is a powerful technique, but also has limitations that should be considered.

  • Genome-wide maps of the chromosomal binding of SMC complexes using ChIP are mostly consistent with the function of these complexes. However, more detailed analysis is required to connect the binding pattern with the many functions of the SMC complexes.

Abstract

Structural maintenance of chromosomes (SMC) complexes, which in eukaryotic cells include cohesin, condensin and the Smc5/6 complex, are central regulators of chromosome dynamics and control sister chromatid cohesion, chromosome condensation, DNA replication, DNA repair and transcription. Even though the molecular mechanisms that lead to this large range of functions are still unclear, it has been established that the complexes execute their functions through their association with chromosomal DNA. A large set of data also indicates that SMC complexes work as intermolecular and intramolecular linkers of DNA. When combining these insights with results from ongoing analyses of their chromosomal binding, and how this interaction influences the structure and dynamics of chromosomes, a picture of how SMC complexes carry out their many functions starts to emerge.

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Figure 1: The functions of SMC complexes.
Figure 2: The chromosomal association of eukaryotic SMC complexes during the cell cycle.
Figure 3: Common binding sites of the SMC complexes determined by ChIP.
Figure 4: Examples of false-positive ChIP signals obtained in budding yeast, and possible three-dimensional conformations inferred from ChIP maps.

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Acknowledgements

This work was financed by the European Research Council, the Swedish Research Council, the Swedish Cancer Society, Karolinska Institute's research foundations and the Swedish Foundation for Strategic Research.

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PowerPoint slides

Glossary

Recombination

The exchange of sequence between two DNA molecules. This starts with a single DNA strand from one molecule invading the other DNA helix. Subsequent DNA synthesis and ligation lead to the formation of DNA links between the two molecules that are resolved at the end of the recombination process.

X chromosome dosage compensation complex

(DCC). A complex involved in the silencing of X chromosomes to equalize gene expression between males and females.

Cornelia de Lange developmental syndrome

Human developmental syndrome caused by mutations in NIPBL (Scc2 homologue), cohesin and the HDAC8 deacetylase.

SUMO

A regulatory peptide, which, when attached to proteins by SUMO ligases, changes the function and/or stability of the modified protein.

Heterochromatin

A highly condensed and transcriptionally less active form of chromatin that occurs at defined sites, such as centromeres, silenced DNA elements or telomeres.

Pre-replication complex

A protein complex that binds and primes origins of replication; chromosome duplication does not occur when the complex is non-functional.

Pericentromeric region

The chromatin region flanking the centromere, which has a strong enrichment of SMC complexes.

Nuclear envelope breakdown

The point at the end of prophase when the nuclear envelope of many eukaryotic cells disassembles.

Sister chromatid intertwinings

DNA entanglements caused by the wrapping of sister chromatids around each other.

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Jeppsson, K., Kanno, T., Shirahige, K. et al. The maintenance of chromosome structure: positioning and functioning of SMC complexes. Nat Rev Mol Cell Biol 15, 601–614 (2014). https://doi.org/10.1038/nrm3857

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