The many functions of smc proteins in chromosome dynamics

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Abstract
The six highly conserved structural maintenance of chromosomes (SMC) proteins form three types of heterodimer (SMC1–SMC3, SMC2–SMC4, SMC5–SMC6), which are core components of large multiprotein complexes. The best known complexes are cohesin, which is responsible for sister-chromatid cohesion, and condensin, which is required for full chromosome condensation in mitosis. Two variants of cohesin exist that differ in a non-SMC subunit. SMC proteins share five conserved domains. The amino-terminal domain contains a Walker A box, an NTP-binding motif, and, at the carboxyl terminus is a DA box with a Walker B-like sequence, and the LSGG signature motif that is typical for the ABC ATPase family of proteins. The central hinge domain, which is flanked by extended coiled–coil regions, is characterized by a set of four highly conserved glycine residues that are typical of flexible regions in a protein. Dimerization of SMC monomers seems to be a function of the hinge domains. Protein interaction and microscopy data suggest that SMC dimers form a ring-like structure, in which the individual SMC protein folds back onto itself, allowing interaction between its amino and carboxyl termini. The ring might embrace DNA molecules. The non-SMC subunits associate with the SMC amino- and carboxy-terminal domains, giving the entire molecule a tadpole-like appearance. Condesin gradually replaces cohesin in mitosis. Resolution of sister-chromatid cohesion requires cleavage of securin (Pds1) to activate separase (Esp1), which cleaves the phosphorylated Scc1 non-SMC subunit of cohesin, triggering its dissociation from the chromosomes. Condensin introduces positive supercoils into relaxed circular DNA, and this is dependent on ATP and topoisomerase I. Knotted DNA is produced if toposiomerase II is present. The knotting activity is stimulated by cyclinB/cdc2 kinase phosphorylation of a non-SMC subunit of condensin. Besides acting in sister-chromatid cohesion and in chromosome condensation, SMC proteins also function in DNA recombination and repair, and — in Caenorhabditis elegans — in gene dosage compensation. SMC proteins and their complexes have also been found in meiotic cells and seem to act in meiotic sister-chromatid cohesion, condensation, and probably in DNA recombination. A meiosis-specific isoform of SMC1 has been described that largely replaces the canonical SMC1. Similarly, there are meiosis-specific variants of non-SMC subunits — for example the Rec8 protein.