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PubMed2006

Condensin is required for chromosome arm cohesion during mitosis.

We describe a novel requirement for the condensin complex in sister chromatid cohesion in Saccharomyces cerevisiae. Strikingly, condensin-dependent cohesion can be distinguished from cohesin-based pairing by a number of criteria. First, condensin is required to maintain cohesion at several chromosomal arm sites but, in contrast to cohesin, is not required at either centromere or telomere-proximal loci. Second, condensin-dependent interlinks are established during mitosis independently of DNA replication and are reversible within a single cell cycle. Third, the loss of condensin-dependent linkages occurs without affecting cohesin levels at the separated URA3 locus. We propose that, during mitosis, robust sister chromatid cohesion along chromosome arms requires both condensinand cohesin-dependent mechanisms, which function independently of each other. We discuss the implications of our results for current models of sister chromatid cohesion.

Adenosine Triphosphatases↗
PubMed2006

Condensin loaded onto the replication fork barrier site in the rRNA gene repeats during S phase in a FOB1-dependent fashion to prevent contraction of a long repetitive array in Saccharomyces cerevisiae.

An average of 200 copies of the rRNA gene (rDNA) is clustered in a long tandem array in Saccharomyces cerevisiae. FOB1 is known to be required for expansion/contraction of the repeats by stimulating recombination, thereby contributing to the maintenance of the average copy number. In Deltafob1 cells, the repeats are still maintained without any fluctuation in the copy number, suggesting that another, unknown system acts to prevent repeat contraction. Here, we show that condensin acts together with FOB1 in a functionally complemented fashion to maintain the long tandem repeats. Six condensin mutants possessing severely contracted rDNA repeats were isolated in Deltafob1 cells but not in FOB1+ cells. We also found that the condensin complex associated with the nontranscribed spacer region of rDNA with a major peak coincided with the replication fork barrier (RFB) site in a FOB1-dependent fashion. Surprisingly, condensin association with the RFB site was established during S phase and was maintained until anaphase. These results indicate that FOB1 plays a novel role in preventing repeat contraction by regulating condensin association and suggest a link between replication termination and chromosome condensation and segregation.

Adenosine Triphosphatases↗
PubMed2005

Drosophila CAP-D2 is required for condensin complex stability and resolution of sister chromatids.

The precise mechanism of chromosome condensation and decondensation remains a mystery, despite progress over the last 20 years aimed at identifying components essential to the mitotic compaction of the genome. In this study, we analyse the localization and role of the CAP-D2 non-SMC condensin subunit and its effect on the stability of the condensin complex. We demonstrate that a condensin complex exists in Drosophila embryos, containing CAP-D2, the anticipated SMC2 and SMC4 proteins, the CAP-H/Barren and CAP-G (non-SMC) subunits. We show that CAP-D2 is a nuclear protein throughout interphase, increasing in level during S phase, present on chromosome axes in mitosis, and still present on chromosomes as they start to decondense late in mitosis. We analysed the consequences of CAP-D2 loss after dsRNA-mediated interference, and discovered that the protein is essential for chromosome arm and centromere resolution. The loss of CAP-D2 after RNAi has additional downstream consequences on the stability of CAP-H, the localization of DNA topoisomerase II and other condensin subunits, and chromosome segregation. Finally, we discovered that even after interfering with two components important for chromosome architecture (DNA topoisomerase II and condensin), chromosomes were still able to compact, paving the way for the identification of further components or activities required for this essential process.

Adenosine Triphosphatases↗
PubMed2006

Misregulated chromosome condensation in MCPH1 primary microcephaly is mediated by condensin II.

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by marked reduction in brain size and mental retardation. Mutations in the gene MCPH1, encoding microcephalin, cause MCPH and a unique cellular phenotype with premature chromosome condensation in early G2 phase and delayed decondensation post mitosis. Here, we show that in MCPH1 patient cells, siRNA-mediated depletions of condensin II subunits lead to a pronounced reduction of cells with the condensation defects in both G1 and G2 phases of the cell cycle. Similar results are obtained when microcephalin and condensin II are simultaneously depleted in HeLa cells. In contrast, depletions of condensin I subunits do not reverse the cellular phenotype. Consistently, condensin I stays in the cytoplasm in the prophase-like cells of MCPH1 patients. Our results offer a molecular explanation for the aberrant chromosome condensation in MCPH1-deficiency and provide additional evidence that condensin I and II are regulated by distinct pathways.

Adenosine Triphosphatases↗
PubMed1997

ATP-dependent positive supercoiling of DNA by 13S condensin: a biochemical implication for chromosome condensation.

13S condensin is a five-subunit protein complex that plays a central role in mitotic chromosome condensation in Xenopus egg extracts. Two core subunits of this complex, XCAP-C and XCAP-E, belong to an emerging family of putative ATPases, the SMC family. We report here that 13S condensin has a DNA-stimulated ATPase activity and exhibits a high affinity for structured DNAs such as cruciform DNA. 13S condensin is able to introduce positive supercoils into a closed circular DNA in the presence of bacterial or eukaryotic topoisomerase I. The supercoiling reaction is ATP-dependent. We propose that 13S condensin wraps DNA in a right-handed direction by utilizing the energy of ATP hydrolysis. This reaction may represent a key mechanism underlying the compaction of chromatin fibers during mitosis.

Adenosine Triphosphatases↗
PubMed2002

Efficient supercoiling of DNA by a single condensin complex as revealed by electron spectroscopic imaging.

Condensin, a five-subunit protein complex essential for mitotic chromosome condensation from yeast to humans, introduces positive supercoils into DNA in an ATP-dependent manner in vitro. We report here the direct visualization of this supercoiling reaction by electron spectroscopic imaging. In the presence of ATP, a single condensin complex is capable of introducing two or more compensatory supercoils into the protein-free region of a closed circular DNA. Within the condensin-bound region, approximately 190 bp of DNA is organized into a compact structure with two distinct domains, indicative of the formation of two oriented gyres. The current results suggest that the action of condensin is more dynamic and more efficient than that postulated before, providing fundamental insight into the energy-dependent mechanism of higher order chromatin folding.

Adenosine Triphosphatases↗
PubMed2026

Condensin accelerates long-range intra-chromosomal interactions.

The 3D genome organization plays a key role in regulating interactions among chromosomal loci. While Chromosome Conformation Capture (3C)-based methods have provided static snapshots of chromatin architecture, the kinetics of chromosomal encounters in live cells remain poorly characterized. In this study, we employ Chemically Induced Chromosomal Interaction (CICI) to measure encounter times between multiple loci pairs in G1-arrested budding yeast. Our results show that chromosome motion closely follows the Rouse polymer model, with similar diffusion parameters at all tested loci. Surprisingly, we find that long-range intra-chromosomal encounters occur significantly faster than inter-chromosomal encounters at similar 3D distances. Using targeted depletion experiments, we identify condensin, but not cohesin, as the complex mostly responsible for these rapid intra-chromosomal interactions. This is further supported by Hi-C analysis, which reveals that condensin promotes long-distance intra-chromosomal interactions in G1 yeast. Through polymer simulations, we estimate that condensin extrudes chromatin at ~2 kb/s with a density of one complex per 1-2 Mb and a processivity of 120-220 kb. These findings uncover a novel role for condensin in shaping the interphase genome organization and provide new insights into chromosomal search dynamics in vivo.

Saccharomyces cerevisiae↗
PubMed2004

Condensin restructures chromosomes in preparation for meiotic divisions.

The production of haploid gametes from diploid germ cells requires two rounds of meiotic chromosome segregation after one round of replication. Accurate meiotic chromosome segregation involves the remodeling of each pair of homologous chromosomes around the site of crossover into a highly condensed and ordered structure. We showed that condensin, the protein complex needed for mitotic chromosome compaction, restructures chromosomes during meiosis in Caenorhabditis elegans. In particular, condensin promotes both meiotic chromosome condensation after crossover recombination and the remodeling of sister chromatids. Condensin helps resolve cohesin-independent linkages between sister chromatids and alleviates recombination-independent linkages between homologues. The safeguarding of chromosome resolution by condensin permits chromosome segregation and is crucial for the formation of discrete, individualized bivalent chromosomes.

Adenosine Triphosphatases↗
PubMed2002

Cohesin release is required for sister chromatid resolution, but not for condensin-mediated compaction, at the onset of mitosis.

The establishment of metaphase chromosomes is an essential prerequisite of sister chromatid separation in anaphase. It involves the coordinated action of cohesin and condensin, protein complexes that mediate cohesion and condensation, respectively. In metazoans, most cohesin dissociates from chromatin at prophase, coincident with association of condensin. Whether loosening of cohesion at the onset of mitosis facilitates the compaction process, resolution of the sister chromatids, or both, remains unknown. We have found that the prophase release of cohesin is completely blocked when two mitotic kinases, aurora B and polo-like kinase (Plx1), are simultaneously depleted from Xenopus egg extracts. Condensin loading onto chromatin is not affected under this condition, and rod-shaped chromosomes are produced that show an apparently normal level of compaction. However, the resolution of sister chromatids within these chromosomes is severely compromised. This is not because of inhibition of topoisomerase II activity that is also required for the resolution process. We propose that aurora B and Plx1 cooperate to destabilize the sister chromatid linkage through distinct mechanisms that may involve phosphorylation of histone H3 and cohesin, respectively. More importantly, our results strongly suggest that cohesin release at the onset of mitosis is essential for sister chromatid resolution but not for condensin-mediated compaction.

Adenosine Triphosphatases↗
PubMed2002

C. elegans condensin promotes mitotic chromosome architecture, centromere organization, and sister chromatid segregation during mitosis and meiosis.

Chromosome segregation and X-chromosome gene regulation in Caenorhabditis elegans share the component MIX-1, a mitotic protein that also represses X-linked genes during dosage compensation. MIX-1 achieves its dual roles through interactions with different protein partners. To repress gene expression, MIX-1 acts in an X-chromosome complex that resembles the mitotic condensin complex yet lacks chromosome segregation function. Here we show that MIX-1 interacts with a mitotic condensin subunit, SMC-4, to achieve chromosome segregation. The SMC-4/MIX-1 complex positively supercoils DNA in vitro and is required for mitotic chromosome structure and segregation in vivo. Thus, C. elegans has two condensin complexes, one conserved for mitosis and another specialized for gene regulation. SMC-4 and MIX-1 colocalize with centromere proteins on condensed mitotic chromosomes and are required for the restricted orientation of centromeres toward spindle poles. This cell cycle-dependent localization requires AIR-2/AuroraB kinase. Depletion of SMC-4/MIX-1 causes aberrant mitotic chromosome structure and segregation, but not dramatic decondensation at metaphase. Moreover, SMC-4/MIX-1 depletion disrupts sister chromatid segregation during meiosis II but not homologous chromosome segregation during meiosis I, although both processes require chromosome condensation. These results imply that condensin is not simply required for compaction, but plays a more complex role in chromosome architecture that is essential for mitotic and meiotic sister chromatid segregation.

Adenosine Triphosphatases↗
PubMed2003

Condensin-dependent localisation of topoisomerase II to an axial chromosomal structure is required for sister chromatid resolution during mitosis.

Assembly of compact mitotic chromosomes and resolution of sister chromatids are two essential processes for the correct segregation of the genome during mitosis. Condensin, a five-subunit protein complex, is thought to be required for chromosome condensation. However, recent genetic analysis suggests that condensin is only essential to resolve sister chromatids. To study further the function of condensin we have depleted DmSMC4, a subunit of the complex, from Drosophila S2 cells by dsRNA-mediated interference. Cells lacking DmSMC4 assemble short mitotic chromosomes with unresolved sister chromatids where Barren, a non-SMC subunit of the complex is unable to localise. Topoisomerase II, however, binds mitotic chromatin after depletion of DmSMC4 but it is no longer confined to a central axial structure and becomes diffusely distributed all over the chromatin. Furthermore, cell extracts from DmSMC4 dsRNA-treated cells show significantly reduced topoisomerase II-dependent DNA decatenation activity in vitro. Nevertheless, DmSMC4-depleted chromosomes have centromeres and kinetochores that are able to segregate, although sister chromatid arms form extensive chromatin bridges during anaphase. These chromatin bridges do not result from inappropriate maintenance of sister chromatid cohesion by DRAD21, a subunit of the cohesin complex. Moreover, depletion of DmSMC4 prevents premature sister chromatid separation, caused by removal of DRAD21, allowing cells to exit mitosis with chromatin bridges. Our results suggest that condensin is required so that an axial chromatid structure can be organised where topoisomerase II can effectively promote sister chromatid resolution.

Adenosine Triphosphatases↗
PubMed2003

Condensin and biological role of chromosome condensation.

Mitotic chromosome condensation is an essential cellular function ensuring proper compaction and segregation of sister chromatids during cell division. Condensin, a five-subunit complex, conserved among eukaryotes, is the key molecular machine of chromosome condensation. Recent advances in the structural biology and functional analysis of condensin demonstrate the unique nature and indispensable biological role of this complex. Condensin functions span chromosome dynamics during mitotic cell division, cell-cycle feedback control mechanisms, as well as formation and maintenance of interphase chromosome structure. Being at the intersection of several cell-cycle regulatory networks condensin is a promising therapeutic target for control over cell proliferation.

Adenosine Triphosphatases↗
PubMed2005

Chromosome morphogenesis: condensin-dependent cohesin removal during meiosis.

During meiosis, segregation of homologous chromosomes necessitates the coordination of sister chromatid cohesion, chromosome condensation, and recombination. Cohesion and condensation require the SMC complexes, cohesin and condensin, respectively. Here we use budding yeast Saccharomyces cerevisiae to show that condensin and Cdc5, a Polo-like kinase, facilitate the removal of cohesin from chromosomes prior to the onset of anaphase I when homologs segregate. This cohesin removal is critical for homolog segregation because it helps dissolve the recombination-dependent links between homologs that form during prophase I. Condensin enhances the association of Cdc5 with chromosomes and its phosphorylation of cohesin, which in turn likely stimulates cohesin removal. Condensin/Cdc5-dependent removal of cohesin underscores the potential importance of crosstalk between chromosome structural components in chromosome morphogenesis and provides a mechanism to couple chromosome morphogenesis with other meiotic events.

Adenosine Triphosphatases↗
PubMed2004

Cdc14 and condensin control the dissolution of cohesin-independent chromosome linkages at repeated DNA.

Chromosome segregation is triggered by the cleavage of cohesins by separase. Here we show that in budding yeast separation of the ribosomal DNA (rDNA) and telomeres also requires Cdc14, a protein phosphatase known for its role in mitotic exit. Cdc14 shares this role with the FEAR network, which activates Cdc14 during early anaphase, but not the mitotic exit network, which promotes Cdc14 activity during late anaphase. We further show that CDC14 is necessary and sufficient to promote condensin enrichment at the rDNA locus and to trigger rDNA segregation in a condensin-dependent manner. We propose that Cdc14 released by the FEAR network mediates the partitioning of rDNA by facilitating the localization of condensin thereto. This dual role of the FEAR network in initiating mitotic exit and promoting chromosome segregation ensures that exit from mitosis is coupled to the completion of chromosome segregation.

Adenosine Triphosphatases↗
PubMed2003

Condensin and cohesin: more than chromosome compactor and glue.

Two related protein complexes, cohesin and condensin, are essential for separating identical copies of the genome into daughter cells during cell division. Cohesin glues replicated sister chromatids together until they split at anaphase, whereas condensin reorganizes chromosomes into their highly compact mitotic structure. Unexpectedly, mutations in the subunits of these complexes have been uncovered in genetic screens that target completely different processes. Exciting new evidence is emerging that cohesin and condensin influence crucial processes during interphase, and unforeseen aspects of mitosis. Each complex can perform several roles, and individual subunits can associate with different sets of proteins to achieve diverse functions, including the regulation of gene expression, DNA repair, cell-cycle checkpoints and centromere organization.

Adenosine Triphosphatases↗
PubMed2006

MTB, the murine homolog of condensin II subunit CAP-G2, represses transcription and promotes erythroid cell differentiation.

Chromosome condensation is essential for proper segregation of duplicated sister chromatids in mitosis. Mammalian erythroid maturation is also associated with gradual nuclear condensation. However, few proteins that are directly involved in chromosome condensation during erythropoiesis have been identified. In this report, we show that MTB (more than blood), which was initially isolated in a yeast two-hybrid screen for proteins that interact with the basic helix-loop-helix (bHLH) protein stem cell leukemia (SCL), and later identified as the murine homolog of the condensin II subunit CAP-G2, participates in erythroid cell development. MTB interacts with SCL and another hematopoietic bHLH protein, E12, and is recruited to the nucleus by SCL and E12. In addition, MTB can repress SCL/E12-mediated transcriptional activation. Consistent with the model that MTB may function together with SCL/E12 heterodimer during erythroid cell development, MTB is highly expressed in the erythroid lineage and is upregulated upon erythroid differentiation. Moreover, overexpression of MTB promotes the terminal differentiation of the murine erythroleukemia erythroid cell line. Together, these findings demonstrate that the condensin II subunit MTB/mCAP-G2 plays a novel function during erythropoiesis and suggest that key hematopoietic transcription factors such as SCL and E12 may regulate the terminal differentiation of hematopoietic cells through the interaction with condensin complexes.

Adenosine Triphosphatases↗
PubMed2000

Dual roles of the 11S regulatory subcomplex in condensin functions.

Condensin is a multisubunit protein complex that reconfigures DNA structure in an ATP-dependent manner in vitro and plays a central role in mitotic chromosome condensation in Xenopus egg cell-free extracts. The Xenopus 13S condensin complex (13SC) is composed of two subcomplexes: an 8S core subcomplex (8SC) consisting of two structural maintenance of chromosomes (SMC) subunits (XCAP-C and -E) and an 11S regulatory subcomplex (11SR) containing three non-SMC subunits (XCAP-D2, -G, and -H). We report here the biochemical and functional dissection of this chromosome condensation machinery. Although both 8SC and 13SC can bind to DNA in vitro and contain the SMC ATPase subunits, only 13SC is active as a DNA-stimulated ATPase and supports ATP-dependent supercoiling activity. In the cell-free extracts, 13SC is the active form that binds to chromosomes and induces their condensation. Neither 11SR nor 8SC alone is able to bind to chromatin. Our results suggest that the non-SMC subunits have dual roles in the regulation of condensin functions: one is to activate SMC ATPases and the other is to allow the holocomplex to associate with chromatin in a mitosis-specific manner.

Adenosine Triphosphatases↗
PubMed2005

The Saccharomyces cerevisiae Smc2/4 condensin compacts DNA into (+) chiral structures without net supercoiling.

Smc2/4 forms the core of the Saccharomyces cerevisiae condensin, which promotes metaphase chromosome compaction. To understand how condensin manipulates DNA, we used two in vitro assays to study the role of SMC (structural maintenance of chromosome) proteins and ATP in reconfiguring the path of DNA. The first assay evaluated the topology of knots formed in the presence of topoisomerase II. Unexpectedly, both wild-type Smc2/4 and an ATPase mutant promoted (+) chiral knotting of nicked plasmids, revealing that ATP hydrolysis and the non-SMC condensins are not required to compact DNA chirally. The second assay measured Smc2/4-dependent changes in linking number (Lk). Smc2/4 did not induce (+) supercoiling, but instead induced broadening of topoisomer distributions in a cooperative manner without altering Lk(0). To explain chiral knotting in substrates devoid of chiral supercoiling, we propose that Smc2/4 directs chiral DNA compaction by constraining the duplex to retrace its own path. In this highly cooperative process, both (+) and (-) loops are sequestered (about one per kb), leaving net writhe and twist unchanged while broadening Lk. We have developed a quantitative theory to account for these results. Additionally, we have shown at higher molar stoichiometries that Smc2/4 prevents relaxation by topoisomerase I and nick closure by DNA ligase, indicating that Smc2/4 can saturate DNA. By electron microscopy of Smc2/4-DNA complexes, we observed primarily two protein-laden bound species: long flexible filaments and uniform rings or "doughnuts." Close packing of Smc2/4 on DNA explains the substrate protection we observed. Our results support the hypothesis that SMC proteins bind multiple DNA duplexes.

Adenosine Triphosphatases↗