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PubMed2000

HEAT repeats associated with condensins, cohesins, and other complexes involved in chromosome-related functions.

HEAT repeats correspond to tandemly arranged curlicue-like structures that appear to serve as flexible scaffolding on which other components can assemble. Using sensitive sequence analysis techniques we detected HEAT repeats in various chromosome-associated proteins, including four families of proteins associated with condensins and cohesins, which are nuclear complexes that contain structural maintenance of chromosome (SMC) proteins. Among the proteins detected were the XCAP-D2 and XCAP-G subunits of the Xenopus laevis 13S condensin complex, the Aspergillus BimD and Sordaria macrospora Spo76p proteins, the budding yeast Scc2p protein, and the related Drosophila transcriptional activator Nipped-B. Clathrin adaptor and COP-I coatomer subunits, which function in vesicle coat assembly and were previously noted to share weak sequence similarity to condensin subunits, also contain HEAT repeats. HEAT repeats were also found in the TBP-associated TIP120 protein, a global enhancer of transcription, and in the budding yeast Mot1p protein, which is a member of the SWI2/SNF2 family. SWI2/SNF2 proteins, some of which are helicases, perform diverse roles in transcription control, DNA repair, and chromosome segregation and form chromatin-remodeling complexes. HEAT repeats also were found in dis1-TOG family and cofactor D family microtubule-associated proteins, which, owing to their roles in microtubule dynamics, perform functions related to mitotic progression and chromosome segregation. Hence, our analysis predicts structural features of these proteins and suggests that HEAT repeats may play important roles in chromosome dynamics.

Amino Acid Sequence↗
PubMed1998

Phosphorylation and activation of 13S condensin by Cdc2 in vitro.

13S condensin is a multisubunit protein complex essential for mitotic chromosome condensation in Xenopus egg extracts. Purified 13S condensin introduces positive supercoils into DNA in the presence of topoisomerase I and adenosine triphosphate in vitro. The supercoiling activity of 13Scondensin was regulated by mitosis-specific phosphorylation. Immunodepletion, in vitro phosphorylation, and peptide-mapping experiments indicated that Cdc2 is likely to be the kinase that phosphorylates and activates 13S condensin. Multiple Cdc2 phosphorylation sites are clustered in the carboxyl-terminal domain of the XCAP-D2 (Xenopus chromosome-associated polypeptide D2) subunit. These results suggest that phosphorylation of 13Scondensin by Cdc2 may trigger mitotic chromosome condensation in vitro.

Adenosine Triphosphatases↗
PubMed2003

Nucleolar association of pEg7 and XCAP-E, two members of Xenopus laevis condensin complex in interphase cells.

Cell cycle dynamics and localization of condensins--multiprotein complexes involved in late stages of mitotic chromosome condensation--were studied in Xenopus laevis XL2 cell line. Western blot analysis of synchronized cells showed that the ratio of levels of both pEg7 and XCAP-E to beta-tubulin levels remains almost constant from G1 to M phase. pEg7 and XCAP-E were localized to the mitotic chromosomes and were detected in interphase nuclei. Immunostaining for condensins and nucleolar proteins UBF, fibrillarin and B23 revealed that both XCAP-E and pEg7 are localized in the granular component of the nucleolus. Nucleolar labeling of both proteins is preserved in segregated nucleoli after 6 hours of incubation with actinomycin D (5 mg/ml), but the size of the labeled zone was significantly smaller. The data suggest a novel interphase function of condensin subunits in spatial organization of the nucleolus and/or ribosome biogenesis.

Adenosine Triphosphatases↗
PubMed2002

[Intracellular localization of XCAP-E and pEg7 condensins in normal mitosis and after the treatment inducing artificial changes in structural organization of mitotic chromosomes].

Function of condensin subunits XCAP-E and pEg7 (XCAP-D2) in the formation and maintaining of special organization of mitotic chromosomes has been studied in Xenopus laevis cells (XL-2). The experimental conditions involved blocking chromosomes being in the condensed state in cells treated by cytostatics, or during their reversible artificial decondensation. The latter was induced by incubation of living cells in hypotonic medium. In extensively mollen chromosomes, XCAP-E and pEg7, remained associated with axial regions of chromosomes. In contrast, upon adaptation of cells to hypotonic conditions and recondensation of chromosomes to nearly initial state, both proteins dissociated from chromosomes into the cytoplasm. In K-mitotic cells, after a 3-6 h treatment with nocodazole or taxol, considerable dissociation of XCAP-E and pEg7 from chromosomes was observed without significant changes in overall level of chromosome compactization. Taken together the data suggested that condensins play no important role in maintaining mitotic chromosomes being in condensed state. Rather, it seems probable that mitotic function of condensins may be associated either with the formation of the higher order chromosome structure, and/or segregation of sister chromatids, the processes being tightly linked with chromosome compactization. This paper is in memory of Professor Katherine Le Guellec of Rennes-1 University, who left us in June 2001. Professor Le Guellec initiated this work in Rennes and offered all the possible help that this work be continued in Moscow University. Let the memory of Katherine, a great scientist and sympathetic friend, live for ever in ours hearts.

Animals↗
PubMed2004

Condensin regulates rDNA silencing by modulating nucleolar Sir2p.

The tandem array of ribosomal DNA (rDNA) in Saccharomyces cerevisiae is subjected to transcriptional silencing of RNA polymerase II-transcribed genes. This form of silencing depends on SIR2 and has been tightly linked to the suppression of rDNA recombination and the control of cellular lifespan. Paradoxically, rDNA silencing takes place in the context of an extremely high rate of RNA polymerase I transcription. Because rDNA silencing requires different factors than HMR and telomere silencing, the chromatin structure and the mechanisms of silencing must be fundamentally different. Here we show that yeast condensin organizes the specialized topology of rDNA chromatin. We then demonstrate that this function is necessary for maintaining the correct balance of telomeric and nucleolar Sir2p. Condensin mutants relocalize telomeric Sir2p to rDNA and show histone hyperacetylation at telomeres. Our data reveal the implication of yeast condensin in the arrangement of rDNA repeats into a heterochromatic-like structure that is important for the correct delineation of silencing domains in the nucleus.

Adenosine Triphosphatases↗
PubMed2026

Mitotic chromosomes: from the chromosome scaffold model to condensins and physical forces.

Mitotic chromosome organization and assembly remain fundamental questions in genetics. Since the chromosome scaffold model proposed in 1977 highlighted the role of nonhistone proteins in determining chromosome shape and size, key nonhistone proteins, including condensins and topoisomerase IIα (topoIIα), have been shown to play critical roles in organizing chromosome axes and chromatin loops. Emerging evidence from biochemistry, imaging, and genomics suggests that mitotic chromosome assembly is a dynamic process driven by the interplay of condensin-mediated looping, topoIIα-dependent entanglement/disentanglement, and multiple physical forces, including electrostatic nucleosome interactions, linker histone H1, free Mg2+, and depletion attraction. In this review, we discuss how these mechanisms contribute to chromosome assembly and propose that interphase chromatin domains function as dynamic building blocks of mitotic chromosomes.

chromatin compaction↗
PubMed2004

Mitotic chromosome formation and the condensin paradox.

During cell division, the chromatin is compacted and resolved into discrete mitotic chromosomes whose proper formation is essential for the faithful distribution of the replicated genome to the daughter cells. Chromatin within mitotic chromosomes is packaged in an orderly and reproducible fashion, but the nature of this higher-order structure has remained elusive, as have the mechanisms of its establishment. Here we provide an overview of how the functional dissection of a non-histone protein complex, condensin, has contributed to our understanding of mitotic chromosomes. Recent studies have revealed that mitotic chromosome formation involves two events: chromatin compaction and establishment of a stable intrinsic higher-order structure. Surprisingly, condensin is only required for the second of these events.

Adenosine Triphosphatases↗
PubMed2005

The MukF subunit of Escherichia coli condensin: architecture and functional relationship to kleisins.

The Escherichia coli MukB, MukE, and MukF proteins form a bacterial condensin (MukBEF) that contributes to chromosome management by compacting DNA. MukB is an ATPase and DNA-binding protein of the SMC superfamily; however, the structure and function of non-SMC components, such as MukF, have been less forthcoming. Here, we report the crystal structure of the N-terminal 287 amino acids of MukF at 2.9 A resolution. This region folds into a winged-helix domain and an extended coiled-coil domain that self-associate to form a stable, doubly domain-swapped dimer. Protein dissection and affinity purification data demonstrate that the region of MukF C-terminal to this fragment binds to MukE and MukB. Our findings, together with sequence analyses, indicate that MukF is a kleisin subunit for E. coli condensin and suggest a means by which it may organize the MukBEF assembly.

Adenosine Triphosphatases↗
PubMed2003

Expression and functional dynamics of the XCAP-D2 condensin subunit in Xenopus laevis oocytes.

The 13 S condensin complex plays a crucial role in the condensation and segregation of the two sets of chromosomes during mitosis in vivo as well as in cell-free extracts. This complex, conserved from yeast to human, contains a heterodimer of structural maintenance of chromosome (SMC) family proteins and three additional non-SMC subunits. We have investigated the expression of the non-SMC condensin component XCAP-D2 in Xenopus laevis oocytes. When studied during meiotic maturation, XCAP-D2 starts to accumulate at the time of germinal vesicle breakdown and reaches its maximal amount in metaphase II oocytes. This accumulation is specifically blocked by injection of antisense oligonucleotides. XCAP-D2 antisense-injected oocytes progress normally through meiosis until metaphase II. At this stage, however, chromosomes exhibit architecture defaults, and resolution of sister chromatids is impaired. Surprisingly, in mitotic extracts made from XCAP-D2 knocked-down oocytes, sperm chromatin normally condenses into compacted chromosomes, whereas the amounts of both free and chromosome-bound XCAP-D2 are markedly reduced. This apparent discrepancy is discussed in light of current knowledge on chromosome dynamics.

5' Untranslated Regions↗
PubMed2006

Condensin I recruitment and uneven chromatin condensation precede mitotic cell death in response to DNA damage.

Mitotic cell death (MCD) is a prominent but poorly defined form of death that stems from aberrant mitosis. One of the early steps in MCD is premature mitosis and uneven chromatin condensation (UCC). The mechanism underlying this phenomenon is currently unknown. In this study, we show that DNA damage in cells with a compromised p53-mediated G2/M checkpoint triggers the unscheduled activation of cyclin-dependent kinase 1 (Cdk1), activation and chromatin loading of the condensin I complex, and UCC followed by the appearance of multimicronucleated cells, which is evidence of MCD. We demonstrate that these processes engage some of the players of normal mitotic chromatin packaging but not those that drive the apoptotic chromatin condensation. Our findings establish a link between the induction of DNA damage and mitotic abnormalities (UCC) through the unscheduled activation of Cdk1 and recruitment of condensin I. These results demonstrate a clear distinction between the mechanisms that drive MCD-associated and apoptosis-related chromatin condensation and provide mechanistic insights and new readouts for a major cell death process in treated tumors.

Adenosine Triphosphatases↗
PubMed2002

Mutation of YCS4, a budding yeast condensin subunit, affects mitotic and nonmitotic chromosome behavior.

The budding yeast YCS4 gene encodes a conserved regulatory subunit of the condensin complex. We isolated an allele of this gene in a screen for mutants defective in sister chromatid separation or segregation. The phenotype of the ycs4-1 mutant is similar to topoisomerase II mutants and distinct from the esp1-1 mutant: the topological resolution of sister chromatids is compromised in ycs4-1 despite normal removal of cohesins from mitotic chromosomes. Consistent with a role in sister separation, YCS4 function is required to localize DNA topoisomerase I and II to chromosomes. Unlike its homologs in Xenopus and fission yeast, Ycs4p is associated with chromatin throughout the cell cycle; the only change in localization occurs during anaphase when the protein is enriched at the nucleolus. This relocalization may reveal the specific challenge that segregation of the transcriptionally hyperactive, repetitive array of rDNA genes can present during mitosis. Indeed, segregation of the nucleolus is abnormal in ycs4-1 at the nonpermissive temperature. Interrepeat recombination in the rDNA array is specifically elevated in ycs4-1 at the permissive temperature, suggesting that the Ycs4p plays a role at the array aside from its segregation. Furthermore, ycs4-1 is defective in silencing at the mating type loci at the permissive temperature. Taken together, our data suggest that there are mitotic as well as nonmitotic chromosomal abnormalities associated with loss of condensin function in budding yeast.

Adenosine Triphosphatases↗
PubMed2003

In vitro and in vivo interactions of DNA ligase IV with a subunit of the condensin complex.

Several findings have revealed a likely role for DNA ligase IV, and interacting protein XRCC4, in the final steps of mammalian DNA double-strand break repair. Recent evidence suggests that the human DNA ligase IV protein plays a critical role in the maintenance of genomic stability. To identify protein-protein interactions that may shed further light on the molecular mechanisms of DSB repair and the biological roles of human DNA ligase IV, we have used the yeast two-hybrid system in conjunction with traditional biochemical methods. These efforts have resulted in the identification of a physical association between the DNA ligase IV polypeptide and the human condensin subunit known as hCAP-E. The hCAP-E polypeptide, a member of the Structural Maintenance of Chromosomes (SMC) super-family of proteins, coimmunoprecipitates from cell extracts with DNA ligase IV. Immunofluorescence studies reveal colocalization of DNA ligase IV and hCAP-E in the interphase nucleus, whereas mitotic cells display colocalization of both polypeptides on mitotic chromosomes. Strikingly, the XRCC4 protein is excluded from the area of mitotic chromosomes, suggesting the formation of specialized DNA ligase IV complexes subject to cell cycle regulation. We discuss our findings in light of known and hypothesized roles for ligase IV and the condensin complex.

Adenosine Triphosphatases↗
PubMed2004

RETRACTED: The bacterial condensin MukBEF compacts DNA into a repetitive, stable structure.

Condensins are conserved proteins containing SMC (structural maintenance of chromosomes) moieties that organize and compact chromosomes in an unknown mechanism essential for faithful chromosome partitioning. We show that MukBEF, the condensin in Escherichia coli, cooperatively compacts a single DNA molecule into a filament with an ordered, repetitive structure in an adenosine triphosphate (ATP) binding-dependent manner. When stretched to a tension of approximately 17 piconewtons, the filament extended in a series of repetitive transitions in a broad distribution centered on 45 nanometers. A filament so extended and held at a lower force recondensed in steps of 35 nanometers or its multiples; this cycle was repeatable even in the absence of ATP and free MukBEF. Remarkably, the pattern of transitions displayed by a given filament during the initial extension was identical in every subsequent extension. Hence, after being deformed micrometers in length, each filament returned to its original compact structure without the addition of energy. Incubation with topoisomerase I increased the rate of recondensation and allowed the structure to extend and reform almost reversibly, indicating that supercoiled DNA is trapped in the condensed structure. We suggest a new model for how MukBEF organizes the bacterial chromosome in vivo.

Adenosine Triphosphate↗
PubMed2004

Chromosome shaping by two condensins.

It remains a big challenge in modern cell biology to determine the mechanism by which a discrete set of rod-shaped chromosomes is assembled from an amorphous mass of interphase chromatin. Recent studies start to shed new lights on how this process is actively supported by a class of multiprotein complexes called condensins. In vertebrate cells, two different condensin complexes make distinct mechanistic contributions to determining the shape and integrity of mitotic chromosomes.

Adenosine Triphosphatases↗
PubMed2026

Non-structural maintenance of chromosome condensin I complex subunit H knockdown suppresses malignant progression of esophageal squamous cell carcinoma via the Wnt/β-catenin signaling pathway.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) remains a major cause of cancer-related mortality, and effective therapeutic targets are still limited. Non-structural maintenance of chromosome condensin I complex subunit H (NCAPH) has been implicated in tumorigenesis; however, its clinical relevance, functional roles, and underlying mechanisms in ESCC are not fully defined. We aimed to characterize the expression pattern, prognostic value, biological functions, and mechanistic basis of NCAPH in ESCC. METHODS: Public datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to evaluate NCAPH expression and clinical associations. Single-cell RNA sequencing (scRNA-seq) data were used to map cell-type-specific distribution of NCAPH in tumor and adjacent tissues. NCAPH was silenced in KYSE150 and KYSE510 cells using lentiviral short hairpin RNAs (shRNAs), followed by Cell Counting Kit-8 (CCK-8), colony formation, wound-healing, and Transwell migration/invasion assays. A nude mouse xenograft model was established to assess the effect of NCAPH knockdown in vivo. RNA sequencing (RNA-seq), quantitative polymerase chain reaction (qPCR), western blotting, and enzyme-linked immunosorbent assay (ELISA) were performed to explore potential mechanisms. RESULTS: NCAPH was consistently upregulated in ESCC across multiple cohorts and was associated with unfavorable clinicopathological features and poorer survival. Functional assays demonstrated that NCAPH knockdown significantly inhibited ESCC cell proliferation, migration, invasion, and clonogenic growth. In vivo, NCAPH silencing suppressed xenograft tumor growth. Mechanistically, transcriptomic profiling and molecular validation indicated attenuation of Wnt/β-catenin signaling following NCAPH depletion, accompanied by reduced β-catenin and downstream targets. CONCLUSIONS: NCAPH promotes malignant progression of ESCC, at least in part through activation of the Wnt/β-catenin pathway, and may serve as a potential biomarker and therapeutic target.

Esophageal squamous cell carcinoma (ESCC)↗
PubMed2004

The Drosophila melanogaster condensin subunit Cap-G interacts with the centromere-specific histone H3 variant CID.

The centromere-specific histone H3 variant CENP-A plays a crucial role in kinetochore specification and assembly. We chose a genetic approach to identify interactors of the Drosophila CENP-A homolog CID. Overexpression of cid in the proliferating eye imaginal disk results in a rough eye phenotype, which is dependent on the ability of the overexpressed protein to localize to the kinetochore. A screen for modifiers of the rough eye phenotype identified mutations in the Drosophila condensin subunit gene Cap-G as interactors. Yeast two-hybrid experiments also reveal an interaction between CID and Cap-G. While chromosome condensation in Cap-G mutant embryos appears largely unaffected, massive defects in sister chromatid segregation occur during mitosis. Taken together, our results suggest a link between the chromatin condensation machinery and kinetochore structure.

Adenosine Triphosphatases↗
PubMed2002

Condensin and cohesin knockouts in Arabidopsis exhibit a titan seed phenotype.

The titan (ttn) mutants of Arabidopsis exhibit striking alterations in chromosome dynamics and cell division during seed development. Endosperm defects include aberrant mitoses and giant polyploid nuclei. Mutant embryos differ in cell size, morphology and viability, depending on the locus involved. Here we demonstrate that three TTN genes encode chromosome scaffold proteins of the condensin (SMC2) and cohesin (SMC1 and SMC3) classes. These proteins have been studied extensively in yeast and animal systems, where they modulate chromosome condensation, chromatid separation, and dosage compensation. Arabidopsis contains single copies of SMC1 and SMC3 cohesins. We used forward genetics to identify duplicate T-DNA insertions in each gene. These mutants (ttn7 and ttn8) have similar titan phenotypes: giant endosperm nuclei and arrested embryos with a few small cells. A single SMC2 knockout (ttn3) was identified and confirmed by molecular complementation. The weak embryo phenotype observed in this mutant may result from expression of a related gene (AtSMC2) with overlapping functions. Further analysis of titan mutants and the SMC gene family in Arabidopsis should provide clues to chromosome mechanics in plants and insights into the regulation of nuclear activity during endosperm development.

Adenosine Triphosphatases↗
PubMed2003

Biochemical analysis of the yeast condensin Smc2/4 complex: an ATPase that promotes knotting of circular DNA.

To better understand the contributions that the structural maintenance of chromosome proteins (SMCs) make to condensin activity, we have tested a number of biochemical, biophysical, and DNA-associated attributes of the Smc2p-Smc4p pair from budding yeast. Smc2p and Smc4p form a stable heterodimer, the "Smc2/4 complex," which upon analysis by sedimentation equilibrium appears to reversibly self-associate to form heterotetramers. Individually, neither Smc2p nor Smc4p hydrolyzes ATP; however, ATPase activity is recovered by equal molar mixing of both purified proteins. Hydrolysis activity is unaffected by the presence of DNA. Smc2/4 binds both linearized and circular plasmids, and the binding appears to be independent of adenylate nucleotide. High mole ratios of Smc2/4 to plasmid promote a geometric change in circular DNA that can be trapped as knots by type II topoisomerases but not as supercoils by a type I topoisomerase. Binding titration analyses reveal that two Smc2/4-DNA-bound states exist, one disrupted by and one resistant to salt challenge. Competition-displacement experiments show that Smc2/4-DNA-bound species formed at even high protein to DNA mole ratios remain reversible. Surprisingly, only linear and supercoiled DNA, not nicked-circular DNA, can completely displace Smc2/4 prebound to a labeled, nicked-circular DNA. To explain this geometry-dependent competition, we present two models of DNA binding by SMCs in which two DNA duplexes are captured within the inter-coil space of an Smc2/4 heterodimer. Based on these models, we propose a DNA displacement mechanism to explain how differences in geometry could affect the competitive potential of DNA.

Adenosine Triphosphatases↗