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Thisleads to more M-Cdk activation, and so on. Such a mechanism would quicklypromote the complete activation of all the M-Cdk complexes in the cell. Asmentioned earlier, similar molecular switches operate at various points in thecell cycle to promote the abrupt and complete transition from one cell-cyclestate to the next.forCondensinHelpsConfigureDuplicatedChromosomesSeparationAt the end of S phase, the immensely long DNA molecules of the sister chromatids are tangled in a mass of partially catenated DNA and proteins.
Anyattempt to pull the sisters apart in this state would undoubtedly lead to breaksin the chromosomes.To avoid this disaster,the cell devotes a great deal of energyin early mitosis to gradually reorganizing the sister chromatids into relativelyshort, distinct structures that can be pulled apart more easily in anaphase.Thesechromosomal changes involve two processes: chromosome condensation, inwhich the chromatids are dramatically compacted; and sister-chromatid resolution, whereby the two sisters are resolved into distinct, separable units (Figure17-26). Resolution results from the decatenation of the sister DNAs, accompanied by the partial removal of cohesin molecules along the chromosome arms.As a result, when the cell reachesmetaphase,the sister chromatids appear in themicroscope as compact, rod-like structures that are joined tightly at their centromeric regions and only loosely along their arms.The condensation and resolution of sister chromatids depends, at least inpart, on a five-subunit protein complex called condensin.
Condensin structureis related to that of the cohesin complex that holds sister chromatids together(seeFigure 17-24).It contains two SMC subunits like those of cohesin, plus threenon-SMC subunits (Figure 17-27). Condensin may form a ring-like structurethat somehow uses the energy provided byATP hydrolysis to promote the compaction and resolution of sister chromatids. Condensin is able to change thecoiling of DNA molecules in a test tube, and this coiling activity is thought to beimportant for chromosome condensation during mitosis.
Interestingly, phosphorylation of condensin subunits by M-Cdk stimulates this coiling activity,providing one mechanism by which M-Cdk may promote chromosome restructuring in early mitosis.1*ATPasedomainMachineTheMitoticSpindlels a Microtubule-BasedThe central event of mitosis-chromosome segregation-depends in all eucaryotes on a complex and beautiful machine called the mitotic spindle. The spindle is a bipolar array of microtubules, which pulls sister chromatids apart inanaphase,thereby segregatingthe two sets of chromosomes to opposite ends ofthe cell, where they are packaged into daughter nuclei.
M-Cdk triSgers theassembly of the spindle early in mitosis, in parallel with the chromosomerestructuring just described. Before we consider how the spindle assemblesandhow its microtubules attach to sister chromatids, we briefly review the basic features of spindle structure.As discussed in Chapter 16, the core of the mitotic spindle is a bipolar arrayof microtubules, the minus ends of which are focused at the two spindle poles,and the plus ends of which radiate outward from the poles (Figure 17-28).<GTCT> The plus ends of some microtubules-called the interpolar microtubules-interact with the plus ends of microtubules from the other pole,resulting in an antiparallel array in the spindle midzone.
The plus ends of otherDNAFigure 17-27 Condensin.Condensinis afive-subunitproteincomplexthatcohesin(seeFigure17-24).resemblesThe head domainsof its two majorsubunits,5mc2and Smc4,areheldtogetherby threeadditionalsubunits.lttheis not clearhow condensincatalyzesand comPactionofrestructuringchromosomeDNA,but it mayform a ringloopsof DNAasstructurethat encirclesshown;it can hydrolyzeATPand coil DNAmoleculesin a testtube.1076Chapter17:TheCellCyclespindlepole replicatedchromosome(sisterchromatids)centro50meFigure17-28 The three classesofmicrotubulesof the mitotic spindleinan animalcell.The plusendsof themicrotubulesprojectawayfrom thecentrosomes,whilethe minusendsareanchoredat the spindlepoles,whichinthis exampleareorganizedbycentrosomes.Kinetochoremicrotubulesconnectthe spindlepoleswith thekinetochoresof sisterchromatids,whileinterpolarmicrotubulesfrom the twopolesinterdigitateat the spindleequator.Astralmicrotubulesradiateout from thepolesinto the cytoplasmand usuallyinteractwith the cellcortex,helpingtopositionthe spindlein the cell.kinetochore,/motor+ proternastral microtubules kinetochoremicrotubulesinteroolar microtubulesmicrotubules-the kinetochore microtubules-are attached to sister chromatid pairs at large protein structures called kinetochores,which are located atthe centromere of each sister chromatid.
Finally, many spindles also containastral microtubules that radiate outward from the poles and contact the cellcortex, helping to position the spindle in the cell.In most somatic animal cells, each spindle pole is focused at a proteinorganelle called the centrosome (discussed in chapter l6). Each centrosomeconsists of a cloud of amorphous material (called the pericentriolar matrix) thatsurrounds a pair of centrioles (Figure lz-29). The pericentriolar matrix nucleates a radial array of microtubules, with their fast-growing plus ends projectingoutward and their minus ends associatedwith the centrosome. The matrix contains a variety of proteins, including microtubule-dependent motor proteins,lpmmicrotubulep e r i c e n t r i o l amr atrix pairof centriolesFigure| 7-29 The centrosome.(A)Electronmicrographof an S-phasemammaliancellin culture,showinga duplicatedcentrosome.Eachcentrosomecontainsa pairof centrioles;althoughthecentrioleshaveduplicated,they remaintogetherin a singlecomplex,as shownin the drawingof themicrographin (B).Onecentrioleof eachcentriolepairhasbeencut in crosssection,whilethe otheris cut in longitudinalsection,indicatingthat the two membersof eachpairarealignedat rightanglesto eachother.Thetwo halvesof the replicatedcentrosome,eachconsistingof a centriolepairsurroundedby pericentriolarmatrix,will splitand migrateapartto initiatethe formationof the twopolesof the mitoticspindlewhen the cellentersM phase.(C)Electronmicrographof a centriolepairthat hasbeenisolatedfrom a cell.Thetwo centrioleshavepartlyseparatedduringthe isolationprocedurebut remaintetheredtogetherby fine fibers,whichkeepthe centriolepairtogetheruntil itis time for them to separate.Bothcentriolesarecut longitudinally,and it can now be seenthat thetwo havedifferentstructures:the mothercentrioleis largerand morecomplexthan the daughtercentriole,and onlythe mothercentrioleis associatedwith pericentriolarmatrixthat nucleatesmicrotubules.Eachdaughtercentriolewill matureduringthe next cellcycle,when it will replicatetogiveriseto its own daughtercentriole.(A,from M.
McGill,D.p.Highfield,T.M.MonahanandB.R.Brinkley,J. ultrastruct.Res.57:43-53,1976.with permissionfrom Academicpress;C,fromM. Paintrandet al.,J. Struct.Biol.108107-128,1992.with permissionfrom Elsevier.)200nm1477MlroSlScoiled-coilproteinsthat link the motorsto the centrosome,structuralproteins,and componentsof the cell-cyclecontrol system.Most important, it containsthe y-tubulin ring complex,which is the component mainly responsibleforin Chapter16).nucleatingmicrotubules(discussedSomecells-notably the cellsof higherplantsand the ooc)'tesof many vertebrates-do not have centrosomes,and microtubule-dependentmotor prowith microtubuleminus endsorganizeandteins and other proteinsassociatedfocusthe spindlepoles.Microtubule-DependentMotorProteinsGovernSpindleAssemblyand FunctionThe assembly and function of the mitotic spindle depend on numerous microtubule-dependent motor proteins.
As discussed in Chapter 16, these proteinsbelong to two families-the kinesin-related proteins, which usually movetoward the plus end of microtubules, and dyneins, which move toward theminus end. In the mitotic spindle, these motor proteins generally operate at ornear the ends of the microtubules. Four major types of motor proteins-kinesin5, kinesin-14, kinesins-4and 10, and dynein-are particularly important in spindle assembly and function (Figure f 7-30).Kinesin-S proteins contain two motor domains that interact with the plusends of antiparallel microtubules in the spindle midzone. Because the twomotor domains move toward the plus ends of the microtubules, they slide thetwo antiparallel microtubules past each other toward the spindle poles, forcingthe poles apart.
Kinesin- l4 proteins, by contrast, are minus-end directed motorswith a single motor domain and other domains that can interact with a differentmicrotubule. They can cross-link antiparallel interpolar microtubules at thespindle midzone and tend to pull the poles together. Kinesin-4 and kinesin-10proteins, also called chromokinesins, are plus-end directed motors that associate with chromosome arms and push the attached chromosome away from thepole (or the pole away from the chromosome).
Finally, dyneins are minus-enddirected motors that, together with associatedproteins, organize microtubulesat various cellular locations. They link the plus ends of astral microtubules tocomponents of the actin cytoskeleton at the cell cortex, for example; by movingtoward the minus end of the microtubules, the dgrein motors pull the spindlepoles toward the cell cortex and away from each other.of a BipolarMitoticin the AssemblyTwoMechanismsCollaborateSpindleThe mitotic spindle must have two poles if it is to pull the two sets of sister chromatids to opposite ends of the cell in anaphase. In animal cells, the primaryfocus of this chapter, two mechanisms collaborate to ensure the bipolarity of thespindle.
One depends on the ability of mitotic chromosomes to nucleate andstabilize microtubules and on the ability of the various motor proteins justdescribed to organize microtubules into a bipolar array, with minus endskinesin-14s p i n d l em i c r o t u b u l ek i n e sni - 5centrosomes i s t e rc h r o m a t i d sk i n e s i n - 4 ,01/Figure17-30 Major motor proteinsofofthe spindle.Fourmajorclassesmotor proteinsmicrotubule-dependent(yel/owboxes)contributeto spindleassemblyand function (seetext).Thecoloredarrowsindicatethe directionofmotor movementalonga microtubuleb/uetoward the minusend, and redtowardthe plusend.'ralseue palle)salnqnlol)tt!Jo ^eJelPrpPluMoslrsaleal)nuMou alllosoJluafq)el ateredasol ut6aqsa^leqo/V\laql pue oM] u! sl!ldsxalduo) oql uaLlM'aseqdogl lllun xa;durotW lo 6uruurbaqleurosorluola;6urse ul taqla6o1aso;tureLuarsred oloulua)onrlaq1 z9 i(qpalaldtuo){;;ensnsrolou}ua)ralq6nepa q ] ; o u o r l e 6 u o laaq l ' t l o 1e ; 6 u e]q6u p te pue alotJluo)raqtou q)paJo aseqaql reauanot6o1sur6aqoloulua)relq6nepe'eseqd5 6urrn6 slalaLuol)tr.uana;e Iq aleledasrredeqi;o salouluo)oMl aq]'Lg u! tulod utetla)p lv'uaar6)xuleurrelouluatrradpaleoossepuerPo aloulua)e Jo Slstsuo)aLuosollua)aq1 'uo11e>1;daralotrlua] 1g-21 arn613iir'.
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