Condensins: universal organizers of chromosomes with diverse functions

Abstract

Condensins are multisubunit protein complexes that play a fundamental role in the structural and functional organization of chromosomes in the three domains of life. Most eukaryotic species have two different types of condensin complexes, known as condensins I and II, that fulfill nonoverlapping functions and are subjected to differential regulation during mitosis and meiosis. Recent studies revealed that the two complexes contribute to a wide variety of interphase chromosome functions, such as gene regulation, recombination, and repair. Also emerging are their cell type- and tissue-specific functions and relevance to human disease. Biochemical and structural analyses of eukaryotic and bacterial condensins steadily uncover the mechanisms of action of this class of highly sophisticated molecular machines. Future studies on condensins will not only enhance our understanding of chromosome architecture and dynamics, but also help address a previously underappreciated yet profound set of questions in chromosome biology.

Figure 1.

Molecular architecture and evolution of condensins. (A) Subunit composition of three different condensin complexes. Condensin I (left) and condensin II (center) share the same pair of SMC2 and SMC4 as their core subunits. The SMC dimer has a characteristic V shape with two ATP-binding “head” domains and a “hinge” domain responsible for dimerization. Each of the three non-SMC subunits of condensin I has a distantly related counterpart in those of condensin II. The CAP-H and CAP-H2 subunits belong to the kleisin family of proteins, whereas the CAP-D2, CAP-G, CAP-D3, and CAP-G2 subunits contain HEAT repeats. (Right) C. elegans has a condensin I-like complex (condensin I^DC) that participates in dosage compensation. Condensin I^DC differs from canonical condensin I by only one subunit: DPY-27, an SMC4 variant (SMC4^V), replaces SMC4 in condensin I^DC. (B) Phylogenetic tree of condensins in Eukaryota. Unikonts: (Hs) Homo sapiens (human); (Dm) D. melanogaster (fruit fly); (Ce) C. elegans (nematode); (Sc) S. cerevisiae (budding yeast); (Sp) S. pombe (fission yeast); (Dd) Dictyostelium discoideum (slime mold). Chromalveolates: (Tt) T. thermophila (ciliate); (Pt) Phaeodactylum tricornutum (diatom). Plantae: (At) A. thaliana (green plant); (Cr) Chlamydomonas reinhardtii (green algae); (Cm) Cyanidioschyzon merolae (red algae). Excavates: (Ng) Naegleria gruberi; (Tb) Trypanosoma brucei. The presence of condensins I and II in each species is indicated by the green and red circles, respectively (condensin I^DC is indicated by the light-green circles). The asterisks are added when not all three non-SMC subunits (of condensin I or II) are found in the sequenced regions of each genome, and the numbers indicate the genome size of each species. The composition of the tree was adapted from Koonin (2010) with permission from Elsevier (© 2010).

Figure 2.

Sequential and balancing actions of condensins I and II. (A) Cell cycle dynamics of condensins I and II in mammalian cells (shown from top to right). During G2 phase, condensin II localizes to the nucleus, whereas condensin I is sequestered in the cytoplasm. (G2, bottom) Although little is known about what condensin II does at this stage of the cell cycle, it may counteract cohesin to prepare for mitosis. For simplicity, catenation between sister DNAs is not shown. In prophase, condensin II participates in the early stage of chromosome condensation within the nucleus. After nuclear envelope breakdown (NEBD), condensin I gains access to chromosomes and collaborates with condensin II to assemble fully resolved sister chromatids by metaphase. It has been proposed that condensin II primarily contributes to axial shortening of chromatids (prophase, bottom), whereas condensin I contributes to lateral compaction (metaphase, bottom). How the differential distribution of the two complexes might be re-established upon nuclear envelope assembly at telophase is unknown. Cohesin, condensin I, and condensin II are indicated by the blue, green, and red circles, respectively. The cartoons presented here are intended to emphasize the proposed, differential contributions of condensins I and II to chromosome assembly and are therefore admittedly oversimplified. Clearly, the two condensin complexes do not act in a completely step-wise fashion: Condensin II continues to act in concert with condensin I even after NEBD. (B) A conceptual model of how the balancing actions of condensins I and II might determine chromosome shapes. “Embryonic” chromosomes with a condensin I:II ratio of ∼5:1 are long and thin because condensin I's contribution is predominant. In contrast, “somatic” chromosomes with a ratio of ∼1:1 are short and thick. Further depletion of condensin II from this condition lengthens the chromosomes (1:0), whereas depletion of condensin I widens them (0:1). In the absence of both condensins I and II, only cloud-like, fuzzy masses of chromatin are observed (0:0). Condensins I and II are indicated by the green and red circles, respectively.

Figure 3.

A diverse array of interphase chromosomal functions supported by condensins. (A) Condensin II promotes the disassembly of polytene chromosomes in D. melanogaster. (B) Condensin II antagonizes transvection in D. melanogaster, possibly by restricting physical interactions between homologous chromosomes. (C) In C. elegans hermaphrodites, condensin I^DC associates with both X chromosomes and down-regulates expression of X-linked genes by half, possibly by changing higher-order chromosome structures of the X. (D) S. cerevisiae condensin plays a crucial role in stabilizing the rDNA repeat. (E) S. cerevisiae condensin promotes clustering (and subsequent nucleolar localization) of tRNA genes that are scattered along its genome.

Figure 4.

Molecular mechanisms of action of eukaryotic condensins. (A, panel a) Reannealing assay. The SMC2–SMC4 dimer is able to convert complementary ssDNAs (green dotted line) into dsDNA (blue solid line) in vitro. This reaction does not require ATP binding or hydrolysis. (Panel b) Supercoiling assay. Condensin I introduces positive supercoils into closed circular DNA in the presence of topo I. This reaction requires ATP binding and hydrolysis by the SMC subunits. (Panel c) Decatenation assay. Condensin's action allows the accumulation of positive supercoils into catenated circular DNAs in topo II-depleted, mitotically arrested cells. When these templates are purified and incubated with topo II in vitro, they are quickly decatenated before being relaxed. (B) An integrated model of how condensins might promote conformational changes of chromosomes. (Step a) The reannealing activity helps ensure dsDNA, a prerequisite for subsequent coiling steps. (Step b) Introduction of positive superhelical tension into catenated sister DNAs promotes topo II-mediated decatenation, thereby facilitating the resolution of sister chromatids. (Step c) Continued positive supercoiling of the decatenated (and therefore liberated) sister DNAs helps the formation of chiral loops. (Step d) Oligomerization or higher-order assembly of condensins might further facilitate and stabilize ordered folding of chromatin fibers, eventually leading to the assembly of sister chromatid axes. It is most likely that the four steps depicted here are not completely separable from each other and must occur in a spatiotemporally coordinated fashion.