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• W1983243203 abstract "When a eukaryotic cell divides, tension builds at centromeres as spindle forces pull chromosomes toward opposite poles during metaphase. New data show that centromeric chromatin stretches in response to these forces, revealing a mechanical role for chromatin packaging in mitosis. When a eukaryotic cell divides, tension builds at centromeres as spindle forces pull chromosomes toward opposite poles during metaphase. New data show that centromeric chromatin stretches in response to these forces, revealing a mechanical role for chromatin packaging in mitosis. DNA replication yields two identical sister strands, chromatids, which remain associated through cohesion until they separate in mitosis and partition to daughter cells. The microtubule-based mitotic spindle generates force for chromosome segregation. The accuracy of chromosome segregation relies on the attachment of each sister chromatid to spindle microtubules from opposite poles of the spindle (bi-orientation). Centromere-associated structures called kinetochores mechanically link spindle microtubules to chromosomes, permitting force from microtubule-dependent motor proteins — kinesins and dynein — and microtubule polymer disassembly to displace chromosomes. Spindles single-mindedly generate poleward force on kinetochore-bound microtubules throughout all phases of mitosis [1Maiato H. DeLuca J. Salmon E.D. Earnshaw W.C. The dynamic kinetochore-microtubule interface.J. Cell Sci. 2004; 117: 5461-5477Crossref PubMed Scopus (314) Google Scholar]. That is advantageous in anaphase, where it separates chromatids without equivocation. In metaphase, however, that single-minded behavior causes bi-oriented chromosomes to experience poleward force toward opposite poles simultaneously. The resulting tug-of-war generates tension on centromeres that increases the separation between sister kinetochores on each chromosome. Microtubule-dependent stretching of sister kinetochores has been observed for many years [1Maiato H. DeLuca J. Salmon E.D. Earnshaw W.C. The dynamic kinetochore-microtubule interface.J. Cell Sci. 2004; 117: 5461-5477Crossref PubMed Scopus (314) Google Scholar]; however, the compliant element of the chromosome or kinetochore was not known. Data reported recently in Current Biology[2Bouck D.C. Bloom K. Pericentric chromatin is an elastic component of the mitotic spindle.Curr. Biol. 2007; 17: 741-748Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar] indicate that centromeric chromatin stretches in response to spindle force, suggesting an active role for chromatin packaging in mitosis. Centromeres in budding yeast are defined by a unique 125 base-pair DNA sequence [3Cleveland D.W. Mao Y. Sullivan K.F. Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling.Cell. 2003; 112: 407-421Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar]. A nucleosome containing the histone H3 variant Cse4p (CENP-A in mammals) forms on this DNA, and works with other centromere-specific DNA binding proteins to recruit kinetochore components to create the microtubule-attachment site on each chromosome. This centromeric DNA and specialized nucleosome are surrounded by a precisely positioned array of nucleosomes [4Bloom K.S. Carbon J. Yeast centromere DNA is in a unique and highly ordered structured in chromosomes and small circular minichromosomes.Cell. 1982; 29: 305-317Abstract Full Text PDF PubMed Scopus (184) Google Scholar]. The strategic placement of nucleosomes suggests a role for chromatin packaging in mitosis, and Bouck and Bloom [2Bouck D.C. Bloom K. Pericentric chromatin is an elastic component of the mitotic spindle.Curr. Biol. 2007; 17: 741-748Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar] set out to test that idea by examining mitotic spindles in cells with reduced histone densities. They extinguished histone H3 or H4 expression in G1 phase yeast cells using a regulatable promoter and examined cells in the ensuing mitosis. Reducing histone density did not inhibit bipolar spindle assembly in most cells and chromosomes established and maintained bipolar attachments to spindle microtubules. However, both spindle length (pole-to-pole) and the distance between sister kinetochore clusters increased in cells with fewer histones. These size increases were not caused by reductions in cohesin recruitment, but appeared to be caused by spindle forces, because inactivation of either Cin8p or Kip1p kinesin motors led to a significant reduction in both spindle size and sister kinetochore spacing. Importantly, kinetochore clusters in histone-depleted cells continued to oscillate, indicating that spindle and kinetochore dynamics were not adversely affected by reductions in histone density. Shortening of sister kinetochore separation in the Δcin8 and Δkip1 mutant cells suggests that an elastic element in chromatin resists these microtubule-based motors which provide an outward force. Although an inelastic barrier could set a maximum distance for sister kinetochore separation, it would not be expected to provide a force that shortens separation upon decreasing the outward force. As a starting point for the interpretation, chromatin is modeled as a simple spring that obeys Hooke's Law, Fs = –kX, which states that the force exerted by the spring, Fs, is proportional to the distance stretched, X, and a spring constant k. The distance between metaphase sister kinetochores is proposed to be established when a mechanical equilibrium is reached between outward force generators and inward force generators, such as chromatin. On the basis of this model, one possibility is that the chromatin based spring constant decreases upon histone depletion. A second possibility is that chromatin rest length — the total length of DNA available to be stretched outward without appreciable resistance — increases upon histone depletion. Because no significant difference in the amplitude of centromere separation oscillation was observed in the nucleosome-depleted cells, the rest length of pericentric chromatin seems to have increased without changing the spring constant. The pericentric DNA that is extended by microtubule motors during formation of the metaphase spindle is most likely a mixture of random coil B-DNA and ‘beads on a string’ nucleosomes. Higher-order pericentric chromatin, such as a 30 nm fiber, seems to be precluded by the total amount of DNA (∼100 kilobases) that would be required to extend between sister kinetochores (0.84 μm in wild-type cells). Whether this pericentric chromatin structure exists prior to microtubule attachment to the kinetochore, or is gradually ‘peeled-off’ higher-order chromatin that exists in the arm, is not known. In the Bouck and Bloom study [2Bouck D.C. Bloom K. Pericentric chromatin is an elastic component of the mitotic spindle.Curr. Biol. 2007; 17: 741-748Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar], a single position close to the centromere was marked using an array of lac operators (lacO) and GFP-tagged LacI repressor molecules, to show that the chromatin rest length increases upon histone depletion. Marking positions closer to the arm with lacO arrays might eventually help distinguish whether more total DNA is pulled from the arm upon histone depletion, or the existing amount of pericentric chromatin separating the sister kinetochores has simply been extended, or a combination of the two. For each absent nucleosome, DNA gains about 40 nm of extra rest length. Hence, approximately 18 nucleosomes should be lost from the DNA that stretches between sister kinetochores to account for the extra rest length gained upon histone depletion. Histones surrounding the centromere have a relatively fast exchange rate compared to a genome-wide average [5Dion M.F. Kaplan T. Kim M. Buratowski S. Friedman N. Rando O.J. Dynamics of replication-independent histone turnover in budding yeast.Science. 2007; 315: 1405-1408Crossref PubMed Scopus (411) Google Scholar], making it plausible that removal of histones from the general pool could lead to a depletion of nucleosomes from pericentric chromatin. B-form DNA, mono-nucleosomes and nucleosome arrays resist mechanical stress in vitro. The magnitude of these resistant forces is consistent with those generated by metaphase spindles and suggests a molecular model (Figure 1). Very little force (<1 pN) is required to extend a random coil of DNA to a linear stretch of B-DNA [6Smith S.B. Finzi L. Bustamante C. Direct mechanical measurements of the elasticity of single DNA molecules by using magnetic beads.Science. 1992; 258: 1122-1126Crossref PubMed Scopus (1511) Google Scholar] or ‘chromatin rest length.’ As the rest length is reached, the force required to further stretch chromatin increases exponentially. Both mono-nucleosome [7Mihardja S. Spakowitz A.J. Zhang Y. Bustamante C. Effect of force on mononucleosomal dynamics.Proc. Natl. Acad. Sci. USA. 2006; 103: 15871-15976Crossref PubMed Scopus (150) Google Scholar] and multi-nucleosome arrays [8Brower-Toland B.D. Smith C.L. Yeh R.C. Lis J.T. Peterson C.L. Wang M.D. Mechanical disruption of individual nucleosomes reveals a reversible multistage release of DNA.Proc. Natl. Acad. Sci. USA. 2002; 99: 1960-1965Crossref PubMed Scopus (365) Google Scholar] display such exponential increases in force resistance as the chromatin is stretched over the range of approximately 200 nm. The force required to extend each is similar, suggesting that inter-nucleosome interactions provide little resistance to chromatin stretching in the absence of any chromatin associated proteins. The increasing resistance (increasing spring constant) is thought to result from the gradual breaking of DNA-histone interactions [9Luger K. Mader A.W. Richmond R.K. Sargent D.F. Richmond T.J. Crystal structure of the nucleosome core particle at 2.8 A resolution.Nature. 1997; 389: 251-260Crossref PubMed Scopus (6468) Google Scholar] at the outer wraps of the nucleosome (Figure 1). As the force gets higher, ‘rips’ are observed as the outer wrap is displaced from the nucleosome and finally the inner wrap is displaced [7Mihardja S. Spakowitz A.J. Zhang Y. Bustamante C. Effect of force on mononucleosomal dynamics.Proc. Natl. Acad. Sci. USA. 2006; 103: 15871-15976Crossref PubMed Scopus (150) Google Scholar, 8Brower-Toland B.D. Smith C.L. Yeh R.C. Lis J.T. Peterson C.L. Wang M.D. Mechanical disruption of individual nucleosomes reveals a reversible multistage release of DNA.Proc. Natl. Acad. Sci. USA. 2002; 99: 1960-1965Crossref PubMed Scopus (365) Google Scholar]. Importantly, peeling DNA off nucleosome outer wraps is reversible, consistent with the observed properties of the chromatin-based force resisting the outward forces of the microtubule motors on the kinetochore. Future experiments on the measurement of sister kinetochore separation using the Bouck and Bloom [2Bouck D.C. Bloom K. Pericentric chromatin is an elastic component of the mitotic spindle.Curr. Biol. 2007; 17: 741-748Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar] system could test this hypothesis by making mutations in the histone residues that stabilize interaction with the outer wraps of DNA. Other chromatin stabilizing elements including linker histones (H1), peeling of 30 nm fibers, and other chromatin-associated structural proteins have yet to be recapitulated in biophysical studies and could also affect sister kinetochore separation. Regardless of the actual mechanism, the novel finding that a chromatin-based force helps establish the formation of the metaphase spindle is likely to have important implications. Chromatin was once thought to be a passive participant in transcriptional regulation, but now the modification and remodeling of chromatin is known to play a highly active role in gene-specific regulation. The discovery of elastic chromatin at the spindle [2Bouck D.C. Bloom K. Pericentric chromatin is an elastic component of the mitotic spindle.Curr. Biol. 2007; 17: 741-748Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar] suggests that modification and remodeling of chromatin may also play an important role in regulation of chromosome segregation and checkpoint function. Studies in both yeast [10Hsu J.M. Huang J. Meluh P.B. Laurent B.C. The yeast RSC chromatin-remodeling complex is required for kinetochore function in chromosome segregation.Mol. Cell Biol. 2003; 23: 3202-3215Crossref PubMed Scopus (79) Google Scholar] and human cells [11Vries R.G. Bezrookove V. Zuijderduijn L.M. Kia S.K. Houweling A. Oruetxebarria I. Raap A.K. Verrijzer C.P. Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint.Genes Dev. 2005; 19: 665-670Crossref PubMed Scopus (87) Google Scholar] have provided evidence that ATP-dependant chromatin remodeling complexes have a direct role in chromosome segregation. Mutations of the yeast RSC complex, for example, impair chromosome segregation [10Hsu J.M. Huang J. Meluh P.B. Laurent B.C. The yeast RSC chromatin-remodeling complex is required for kinetochore function in chromosome segregation.Mol. Cell Biol. 2003; 23: 3202-3215Crossref PubMed Scopus (79) Google Scholar]. This defect appears to be caused by a defect in RSC mutants depositing cohesin along chromatid arms [12Huang J. Hsu J.M. Laurent B.C. The RSC nucleosome-remodeling complex is required for Cohesin's association with chromosome arms.Mol. Cell. 2004; 13: 739-750Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 13Baetz K.K. Krogan N.J. Emili A. Greenblatt J. Hieter P. The ctf13-30/CTF13 genomic haploinsufficiency modifier screen identifies the yeast chromatin remodeling complex RSC, which is required for the establishment of sister chromatid cohesion.Mol. Cell Biol. 2004; 24: 1232-1244Crossref PubMed Scopus (110) Google Scholar]. Whether RSC or other ATP-dependent chromatin remodeling complexes directly affect the resistance of pericentric chromatin to extension is now open for debate. For example, RSC and SWI/SNF complexes generate significant force when disrupting DNA-histone interactions [14Zhang Y. Smith C.L. Saha A. Grill S.W. Mihardja S. Smith S.B. Cairns B.R. Peterson C.L. Bustamante C. DNA translocation and loop formation mechanism of chromatin remodeling by SWI/SNF and RSC.Mol. Cell. 2006; 24: 559-568Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar], and this force could be harnessed to assist microtubule-based motors. Covalent modification of pericentric chromatin also influences the fidelity of chromosome segregation [15Kanta H. Laprade L. Almutairi A. Pinto I. Suppressor analysis of a histone defect identifies a new function for the hda1 complex in chromosome segregation.Genetics. 2006; 173: 435-450Crossref PubMed Scopus (8) Google Scholar]. These modifications may directly or indirectly influence the resistance to spindle elongation caused by chromatin. Biophysical studies of acetylated nucleosomes suggest that their stability is compromised [16Toth K. Brun N. Langowski J. Chromatin compaction at the mononucleosome level.Biochemistry. 2006; 45: 1591-1598Crossref PubMed Scopus (54) Google Scholar], such that they may provide less resistance to outward forces on sister kinetochores. Finally, tension felt across centromeres is an important mechanical cue that silences the spindle assembly checkpoint [17Pinsky B.A. Biggins S. The spindle checkpoint: tension versus attachment.Trends Cell Biol. 2005; 15: 486-493Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar]. These new data raise the intriguing possibility that chromatin stretching is monitored by checkpoint signaling mechanisms to determine when to initiate anaphase." @default.
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• W1983243203 title "Mitosis: Springtime for Chromatin" @default.
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