Rings, bracelet or snaps: fashionable alternatives for Smc complexes

Abstract

The mechanism of higher order chromosome organization has eluded researchers for over 100 years. A breakthrough occurred with the discovery of multi-subunit protein complexes that contain a core of two molecules from the structural maintenance of chromosome (Smc) family. Smc complexes are important structural components of chromosome organization in diverse aspects of DNA metabolism, including sister chromatid cohesion, condensation, global gene repression, DNA repair and homologous recombination. In these different processes, Smc complexes may facilitate chromosome organization by tethering together two parts of the same or different chromatin strands. The mechanism of tethering by Smc complexes remains to be elucidated, but a number of intriguing topological alternatives are suggested by the unusual structural features of Smc complexes, including their large coiled-coil domains and ATPase activities. Distinguishing between these possibilities will require innovative new approaches.

Figure 1

Chromosome organization during mitosis. During the cell cycle, a chromosome is replicated during S phase. The duplicated copies of the chromosome are called sister chromatids (black and grey). Sister chromatids are held together from the time of replication in S phase until the onset of chromosome segregation during mitosis. This cohesion facilitates bipolar attachment of the sister kinetochores to the microtubules of the mitotic spindle, ensuring the orderly segregation of sister chromatids to opposite poles. At the onset of mitosis, sister chromatids become visibly condensed. Chromosome condensation separates sister chromatids into distinct domains, which facilitates subsequent sister chromatid segregation by the mitotic spindle. Condensation also shortens the length of the sister chromatids, which ensures that they are properly packaged into the dividing cell upon cytokinesis.

Figure 2

Smc complex assembly. A cartoon of an Smc protein is shown on the left. Folding of the Smc molecule at the hinge generates the head domain and brings the Walker A site (important for ATP binding) and Walker B motif (important for ATPase activity) in close proximity to form a functional ATPase. Smc molecules can dimerize through their hinge motifs. The signature motif of each head domain can bind to the ATP associated with the other head domain of the dimer, generating a closed ring. The ring is stabilized by the binding of a kleisin molecule and other non-Smc proteins (not shown). In principle, oligomers of the Smc complex could occur through interactions of the hinge domains or coiled-coil domains. Alternatively, oligomers may form by the signature motif binding to a head domain of another dimer.

Figure 3

Three models for how Smc complexes may tether two DNA molecules/chromatin. Each model shows two strands of DNA/chromatin. These strands may come from two distinct DNA molecules (as expected for recombination or sister chromatid cohesion), or from a single DNA/chromatin molecule that is folded back on itself (as expected for regulation of gene expression or condensation). In the first model, the Smc complex embraces the two DNA strands. The snap model proposes that each Smc complex can bind a single strand and that tethering results from the oligomerization of the Smc complexes. The bracelet model suggests that Smc complexes can oligomerize to form filaments. Such filaments could be used in a number of ways to mediate tethering. One possible mechanism is shown here.