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SMC complexes: from DNA to chromosomes

Key Points

  • A living organism's genomic DNA, which is contained in each cell, is typically far longer than the organism itself. This poses a formidable challenge for DNA compaction in the cell nucleus and its segregation during cell division.

  • Members of the structural maintenance of chromosomes (SMC) family are abundant and universal chromosomal protein components. They take on crucial roles in compacting and segregating both prokaryotic and eukaryotic genomes.

  • SMC complexes are ring-shaped ATPases that bind to chromosomes by topological embrace. They are thought to structure and safeguard chromosomes by engaging in interactions between more than one fragment of DNA. They also recruit and interact with additional chromosomal proteins.

  • The condensin complex may compact chromosomes by providing dynamic links between its binding sites, whereas cohesin has evolved special features to establish enduring links between newly replicated sister chromatids.

  • Mutations in SMC complexes and their regulators are the cause of grave human malignancies, including cancer and developmental disorders.

Abstract

SMC (structural maintenance of chromosomes) complexes — which include condensin, cohesin and the SMC5–SMC6 complex — are major components of chromosomes in all living organisms, from bacteria to humans. These ring-shaped protein machines, which are powered by ATP hydrolysis, topologically encircle DNA. With their ability to hold more than one strand of DNA together, SMC complexes control a plethora of chromosomal activities. Notable among these are chromosome condensation and sister chromatid cohesion. Moreover, SMC complexes have an important role in DNA repair. Recent mechanistic insight into the function and regulation of these universal chromosomal machines enables us to propose molecular models of chromosome structure, dynamics and function, illuminating one of the fundamental entities in biology.

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Figure 1: Architecture of the cohesin ring.
Figure 2: Model for DNA entry into and exit out of the cohesin ring.
Figure 3: SMC complex loading on to chromosomes in vivo.
Figure 4: Condensin in chromosome condensation.
Figure 5: Cohesin in sister chromatid cohesion and DNA repair.

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Acknowledgements

The author would like to thank P. Huis in 't Veld, J.-M. Peters and M. Singleton for contributing unpublished images; J. Murray and J. Palecek for communicating unpublished results; and Y. Murayama, T. Toda and all the members of the author's laboratory for discussions and for critical reading of the manuscript. Work in the author's laboratory is chiefly supported by The Francis Crick Institute and the European Research Council.

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DATABASES

Protein Data Bank (PDB)

1GXL

1W1W

4PK7

4UX3

Glossary

Sister chromatid cohesion

The process by which pairs of DNA replication products, which are synthesized during S phase, remain connected to one another. Sister chromatid cohesion persists throughout G2 and until mitosis, when it forms the basis for the pairwise recognition and bi-orientation of sister chromatids by the mitotic spindle apparatus.

Centromeres

The places on chromosomes at which connections with microtubules are established. Centromeres consist of specialized chromatin on which the kinetochore — a large protein assembly that connects the centromere to spindle microtubules — is assembled.

Bi-orientation

The state in which the two sister centromeres face in opposite directions, attached to microtubules emanating from opposite spindle poles.

Inner kinetochore

The part of the kinetochore that makes contact with the DNA, as opposed to the outer kinetochore, which engages with microtubules.

Pre-replicative complexes

Multi-protein assemblies that exist on chromosomes in preparation for DNA replication, marking the sites at which DNA will unravel and replication will initiate.

Topoisomerase II

An enzyme that transiently cuts both strands of a DNA molecule simultaneously, to allow passage of another DNA molecule, before resealing the gap.

Replication forks

Points at which the DNA double helix is unwound and new DNA is synthesized to replicate chromosomes.

Proliferating cell nuclear antigen

(PCNA). Also known as DNA sliding clamp. A ring-shaped homotrimeric protein that is loaded on to DNA during DNA replication and serves as a processivity factor for DNA polymerases. Also serves as a 'landing pad' for many other enzymes that work on DNA.

Replisome

The entire complement of proteins that form the replication machinery that moves the replication fork along DNA and replicates the chromosomes.

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Uhlmann, F. SMC complexes: from DNA to chromosomes. Nat Rev Mol Cell Biol 17, 399–412 (2016). https://doi.org/10.1038/nrm.2016.30

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