Molecular and Genetic Analysis of Condensin Function in Vertebrate Cells

Hudson, Damien F.; Ohta, Sachio; Freisinger, Tina; MacIsaac, Fiona; Sennels, Lau; Alves, Flávia de Lima; Lai, Fang; Kerr, Alastair; Rappsilber, Juri; Earnshaw, William C.

doi:10.1091/mbc.e08-01-0057

Cited by 55 publications

(59 citation statements)

References 40 publications

(57 reference statements)

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“…However, this is the first report to implicate NVL in cancer biology, and further study is required. SMC4 is an ATPase core protein of the condensin I and II complexes that capture and condense chromatids in the early stages of mitosis (44). SMC4 has been implicated in colorectal, liver, and breast cancer (45-47), but has not been studied in prostate cancer or implicated in the metastatic cascade.…”

Section: Discussionmentioning

confidence: 99%

The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer

Zhao

Evans

Kothari

et al. 2016

Clinical Cancer Research

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Purpose: There is a clear need to improve risk stratification and to identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets.Experimental Design: We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4 years). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score.Results: Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell-cycle progression signature, and CAPRA-S).Conclusions: To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes.

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Section: Discussionmentioning

confidence: 99%

The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer

Zhao

Evans

Kothari

et al. 2016

Clinical Cancer Research

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“…Hudson et al (2003) applied this technique to the condensin core subunit SMC2 (also known as ScII) and showed that it is required for nonhistone protein assembly and structural integrity of mitotic chromosomes. A subsequent mutational study demonstrated that ATP binding, but not hydrolysis, by SMC2 is required for its stable association with chromosomes (Hudson et al 2008). In DT40 cells depleted of SMC2, defects in chromosome condensation are relatively modest in metaphase but become very severe in anaphase, leading to the proposal that a hypothetical factor termed regulator of chromosome architecture (RCA) might cooperate with condensins to preserve the characteristic shape of metaphase chromosomes (Vagnarelli et al 2006).…”

Section: Chicken Dt40 Cellsmentioning

confidence: 99%

“…It is attractive to speculate that whereas cohesin holds two different sister DNA strands together, a single condensin complex might link two distant segments of a sister chromatid to promote its folding and compaction. Indeed, this idea is not incompatible with the chiral looping model of condensin's action, although condensin-DNA interactions are clearly more complex than those predicted from a simple topological entrapment (Stray and Lindsley 2003;Stray et al 2005;Hudson et al 2008).…”

Section: How Might Condensins Work?mentioning

confidence: 99%

Condensins: universal organizers of chromosomes with diverse functions

2012

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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.

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“…Indeed, expression of wild-type SMC2 driven by a fragment of the endogenous SMC2 promoter restored the shorter distance between the two centromere-proximal sister loci in SMC2 OFF :CEN cells (Figure 4e). However, SMC2 S1086R , a mutant capable of assembling a condensin complex that targets to chromosomes (Supplementary Figure S1) but that lacks ATPase activity (Hudson et al, 2008) failed to rescue the spacing between sister kinetochores (Figure 4e). Therefore, normal stiffness of the centromeric chromatin requires SMC2 ATPase activity.…”

Section: Atpase Activity Of Condensin Is Essential For the Maintenancmentioning

confidence: 99%

Condensin Regulates the Stiffness of Vertebrate Centromeres

Ribeiro

Gatlin

Yang

et al. 2009

MBoC

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137

147

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When chromosomes are aligned and bioriented at metaphase, the elastic stretch of centromeric chromatin opposes pulling forces exerted on sister kinetochores by the mitotic spindle. Here we show that condensin ATPase activity is an important regulator of centromere stiffness and function. Condensin depletion decreases the stiffness of centromeric chromatin by 50% when pulling forces are applied to kinetochores. However, condensin is dispensable for the normal level of compaction (rest length) of centromeres, which probably depends on other factors that control higher-order chromatin folding. Kinetochores also do not require condensin for their structure or motility. Loss of stiffness caused by condensindepletion produces abnormal uncoordinated sister kinetochore movements, leads to an increase in Mad2(؉) kinetochores near the metaphase plate and delays anaphase onset. INTRODUCTIONCentromeric chromatin is a special region of chromosomes that has important mechanical and signaling functions in mitosis (Pidoux and Allshire, 2005;Ekwall, 2007;Cheeseman and Desai, 2008;Vagnarelli et al., 2008). In metaphase, pulling forces generated by interactions between spindle microtubules (MTs) and kinetochores are opposed by tension produced by centromeric chromatin stretch. Centromere and kinetochore tension and stretch are important for maintaining chromosome alignment (McIntosh et al., 2002), stabilizing kinetochore microtubule (kMT) attachments (Nicklas and Koch, 1969), spindle checkpoint signaling (Musacchio and Salmon, 2007;McEwen and Dong, 2009), and also for the back-to-back orientation of sister kinetochores (Loncarek et al., 2007). At least three independent factors have roles in the establishment of centromeric tension in metaphase: sister chromatid cohesion (Yeh et al., 2008), the elastic properties of chromatin (Houchmandzadeh et al., 1997;Almagro et al., 2004;Marko, 2008), and the higher order structure of the centromeric chromatin.Condensin is important for the architecture of mitotic chromosome arms (Coelho et al., 2003;Hudson et al., 2003;Hirota et al., 2004;Hirano, 2006), but it also localizes to centromeres (Saitoh et al., 1994;Gerlich et al., 2006), where condensin I, but not condensin II was reported to have a role in stabilizing the structure (Gerlich et al., 2006). It has recently been suggested that condensin could have a role in regulating the elastic behavior of centromeric chromatin. One study found that condensin I-depleted Drosophila chromosomes were unable to align at a metaphase plate, had distorted kinetochore structures, and lost elasticity of their centromeric chromatin (Oliveira et al., 2005). However a similar study in human cells reported that although loss of condensin I caused kinetochores to undergo abnormal movements, these movements were bidirectional (e.g., reversible; Gerlich et al., 2006).Even after the publication of those results, the regulation and functional significance of centromere stretch remained unknown. An elegant study in budding yeast went on to find that chromatin struct...

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Molecular and Genetic Analysis of Condensin Function in Vertebrate Cells

Cited by 55 publications

References 40 publications

The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer

The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer

Condensins: universal organizers of chromosomes with diverse functions

Condensin Regulates the Stiffness of Vertebrate Centromeres

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