Key Points
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
Members of the structural maintenance of chromosomes (SMC) family share a characteristic design and configuration of protein domains that provides the molecular basis for the various functions of this family in chromosome dynamics. SMC proteins have a role in chromosome condensation, sister-chromatid cohesion, DNA repair and recombination, and gene dosage compensation, and they function in somatic and meiotic cells. As more is learned about how their unique design affects their function, a picture of a dynamic and varied protein family is emerging.
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Acknowledgements
I thank members of my laboratory for discussions, in particular E. Revenkova and A. Solovicova for comments on the manuscript. Research in the author's laboratory has been supported by grants from the HFSP and the NIH.
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DATABASES
LocusLink
Saccharomyces genome database
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FURTHER INFORMATION
Glossary
- WALKER A AND B MOTIFS
-
ATP-interaction motifs defined by Walker and colleagues in 1982. The A box contains a P-loop that is involved in phosphate binding; a B-like sequence is contained in the highly conserved DA box at the SMC carboxyl termini and could be involved in binding Mg2+. A and B sites can interact to form an ATP-binding and hydrolysis fold.
- CHROMATIN IMMUNOPRECIPITATION
-
(ChIP). A technique that isolates sequences from soluble DNA chromatin extracts (complexes of DNA and protein) using antibodies that recognize specific chromosomal proteins.
- CATENATION/DECATENATION
-
Topoisomerases catenate (join) or decatenate (separate) two circular DNA molecules by cutting one DNA strand, passing a second strand through the break and resealing the break in DNA.
- DNA POLYMERASE σ
-
One of a series of newly described DNA polymerases. Polσ (previously named Polσ) is required to establish cohesion in S phase. It is the product of the TRF4 gene, which has redundant homologues.
- RNA INTERFERENCE
-
The process by which an introduced double-stranded RNA specifically silences the expression of genes through degradation of their cognate mRNAs.
- DNA LIGASE III
-
One of three DNA ligases found in eukaryotic cells. Acts in repair of single-stranded DNA breaks and forms a complex with the repair gene XRCC1. There is a meiotic isoform, DNA ligase IIIβ.
- DNA POLYMERASE ɛ
-
A DNA polymerase that associates with the replication fork, acts in nucleotide-excision repair, possibly in recombinational repair, and might contribute an S-phase checkpoint function. In yeast the enzyme is not essential for many of these functions.
- NUCLEOTIDE-EXCISION REPAIR
-
The main pathway for removal of UV-damaged bases.
- SYNTHETIC INTERACTIONS
-
These occur when a double mutant has a phenotype different from either single mutant parent. For suppressors (synthetic viable), the double mutant is viable when at least one of the single mutants is not. For synthetic lethal mutants, the double mutant is inviable under conditions in which both parents are viable.
- ATM KINASE
-
The protein that is mutated in ataxia-telangiectasia, with major functions in signal transduction in the response to DNA damage.
- AXIAL ELEMENTS
-
Two axial elements form the side elements of the ladder-like synaptonemal complex. They are connected by numerous transverse filaments along their length. Each axial element supports the two sister chromatids of one homologue.
- SYNAPTONEMAL COMPLEX
-
A characteristic, zipper- or ladder-like protein structure, formed during meiotic prophase between paired homologous chromosomes.
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Jessberger, R. The many functions of smc proteins in chromosome dynamics. Nat Rev Mol Cell Biol 3, 767–778 (2002). https://doi.org/10.1038/nrm930
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DOI: https://doi.org/10.1038/nrm930
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