Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Condensins: universal organizers of chromosomes with diverse functions Tatsuya Hirano1 Chromosome Dynamics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan Condensins are multisubunit protein complexes that Concurrent genetic studies in different model organisms play a fundamental role in the structural and functional provided strong lines of evidence that condensin I is es- organization of chromosomes in the three domains of sential for proper condensation and segregation of chro- life. Most eukaryotic species have two different types of mosomes in vivo. Remarkably, even bacteria and archaea condensin complexes, known as condensins I and II, that turn out to have condensin-like complexes, and many fulfill nonoverlapping functions and are subjected to dif- eukaryotic species have a second condensin complex ferential regulation during mitosis and meiosis. Recent (condensin II). Most recently, ample evidence has been studies revealed that the two complexes contribute to accumulating that condensins’ functions are not limited a wide variety of interphase chromosome functions, such to chromosome condensation and segregation in mitosis as gene regulation, recombination, and repair. Also emerg- (or meiosis): They participate in a wide range of chromo- ing are their cell type- and tissue-specific functions and some functions supporting genome stability, cell differ- relevance to human disease. Biochemical and structural entiation, and development. Hence, condensins are now analyses of eukaryotic and bacterial condensins steadily recognized as universal organizers of chromosomes con- uncover the mechanisms of action of this class of highly served among the three domains of life. In this review, I sophisticated molecular machines. Future studies on summarize and discuss recent progress in the field of condensins will not only enhance our understanding of condensins. Emphasis is placed on the evolutionary land- chromosome architecture and dynamics, but also help ad- scape of the chromosome organizers and the differential dress a previously underappreciated yet profound set of yet coordinated actions of the two different condensin questions in chromosome biology. complexes in eukaryotes. For recent reviews on this topic, see also Hirano (2005), Hudson et al. (2009), and Wood During the past two decades, we have witnessed geno- et al. (2010). mics and epigenomics quickly entering the central stage in biology and immensely transforming our understand- Evolutionary landscape ing of gene functions, cell differentiation, development, biodiversity, and evolution. There is no doubt that this Eukaryota trend will continue. To fully ‘‘decode’’ genomic and epigenomic information, however, understanding their It is currently known that there exist (at least) two dif- three-dimensional organization and dynamics is essen- ferent types of condensin complexes, known as conden- tial. In this sense, elucidation of higher-order chromo- sins I and II, among eukaryotes. The two complexes share some structure will remain at the frontier of modern the same pair of SMC2 and SMC4 subunits, both belong- biology. From a historical point of view, a main branch of ing to the structural maintenance of chromosomes (SMC) chromosome research had focused on structural and family of chromosomal ATPases (Hirano 2006). Each com- biochemical dissection of ‘‘condensed’’ chromosomes plex has a unique set of three non-SMC subunits (i.e., that become visible during cell divisions, eventually CAP-D2, CAP-G, and CAP-H for condensin I, and CAP- leading to the discovery of a class of multisubunit protein D3, CAP-G2, and CAP-H2 for condensin II). CAP-D2 and complexes collectively referred to as condensins. The CAP-D3 (and CAP-G and CAP-G2) are distantly related to founding member of condensins (now known as con- each other and have a degenerated repeat motif called densin I) was identified from Xenopus egg extracts as a ma- HEAT repeats (Neuwald and Hirano 2000). On the other jor component of chromosomes that plays a crucial role hand, CAP-H and CAP-H2 are members of the kleisin in assembling chromosomes in the cell-free extracts. family of SMC-interacting proteins (Schleiffer et al. 2003). Electron microscopic analyses have visualized the highly characteristic architecture of condensin I (Anderson et al. [Keywords: chromosome condensation; sister chromatid separation; 2002), and protein–protein interaction assays using re- condensins; SMC proteins] combinant subunits have revealed the geometry of 1Correspondence E-mail [email protected] the subunits within each complex (Fig. 1A; Onn et al. Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.194746.112. 2007). GENES & DEVELOPMENT 26:1659–1678 Ó 2012 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/12; www.genesdev.org 1659 Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Hirano Condensin I is conserved from yeast to humans (Table condensin II occurred independently multiple times in 1; Hirano et al. 1997; Sutani et al. 1999). When condensin different kingdoms during evolution (Fig. 1B). II was first discovered from vertebrate cells (Ono et al. 2003; Yeong et al. 2003), none of the corresponding sub- Bacteria/archaea units specific to condensin II was found in fungi such as Saccharomyces cerevisiae and Schizosaccharomyces Most if not all species of bacteria and archaea have a single pombe. It was therefore hypothesized that condensin condensin-like complex composed of three subunits: SMC, II might be a new invention in evolution that provided ScpA, and ScpB (hereafter referred to as the SMC–ScpAB an additional level of organization and rigidity for complex) (Graumann and Knust 2009). On the other hand, organisms with large chromosomes (Ono et al. 2003). some species belonging to a subclass of g-proteobacteria, However, information from an ever-growing number of which includes Escherichia coli, have a distinct complex eukaryotic genomes that have been sequenced since composed of MukB, MukE, and MukF (referred to as the then strongly suggests that the original view is wrong. MukBEF complex) instead of SMC–ScpAB (Hiraga 2000). In fact, both condensins I and II are almost ubiquitous Increasing lines of evidence from structural and genetic in eukaryotes, and only a limited number of organisms studies suggest that the MukBEF complex shares some have condensin I only (Fig. 1B). There is no apparent functional properties with SMC–ScpAB, although the relationship between the possession of condensin II and similarities between the corresponding subunits (SMC/ the size of genomes among eukaryotic species. The MukB, ScpA/MukF, and ScpB/MukE) are rather limited implication is that the last common ancestor of eu- at the amino acid sequence level. The core of the bacterial karyotes possessed both condensins I and II and that condensin complex is a homodimer of SMC/MukB sub- some species have lost condensin II during evolution. units, and ScpA/MukF is likely to function as a kleisin Moreover, a phylogenetic tree indicates that loss of (Fennell-Fezzie et al. 2005). The subunit–subunit interac- 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 IDC) that participates in dosage compensation. Condensin IDC differs from canonical condensin I by only one subunit: DPY-27, an SMC4 variant (SMC4V), replaces SMC4 in condensin IDC.(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 IDC 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 (Ó 2010). 1660 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Condensins and chromosome regulation Table 1. Condensin subunits in eukaryotic model organisms D. C. S. S. A. Subunits Vertebrates melanogaster elegans cerevisiae pombe thaliana Core subunits (common to I and II) SMC2 CAP-E/SMC2 SMC2 MIX-1 Smc2 Cut14 CAP-E1 and CAP-E2 SMC4 CAP-C/SMC4 SMC4/Gluon