B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 71
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A cell with only one typeof chromosome, present in maternal andpaternal copies, is illustrated here. OnceDNA replication is complete, the cell canenter M phase, when mitosis occurs andthe nucleus is divided into two daughternuclei. During this stage, the chromosomescondense, the nuclear envelope breaksdown, and the mitotic spindle forms frommicrotubules and other proteins.
Thecondensed mitotic chromosomes arecaptured by the mitotic spindle, and onecomplete set of chromosomes is thenpulled to each end of the cell by separatingthe members of each sister-chromatid pair.A nuclear envelope re-forms around eachchromosome set, and in the final step ofM phase, the cell divides to produce twodaughter cells. Most of the time in the cellcycle is spent in interphase; M phase isbrief in comparison, occupying only aboutan hour in many mammalian cells.mitoticspindlematernal interphase chromosomeGENE EXPRESSIONAND CHROMOSOMEDUPLICATION185MITOSISCELLDIVISIONmitoticchromosomeINTERPHASEM PHASEINTERPHASE186Chapter 4: DNA, Chromosomes, and Genomescorrectly into the two daughter cells.
These basic functions are controlled by threetypes of specialized nucleotide sequences in the DNA, each of which binds specific proteins that guide the machinery that replicates and segregates chromosomes (Figure 4–19).Experiments in yeasts, whose chromosomes are relatively small and easy tomanipulate, have identified the minimal DNA sequence elements responsible foreach of these functions. One type of nucleotide sequence acts as a DNA replication origin, the location at which duplication of the DNA begins. Eukaryoticchromosomes contain many origins of replication to ensure that the entire chromosome can be replicated rapidly, as discussed in detail in Chapter 5.After DNA replication, the two sister chromatids that form each chromosomeremain attached to one another and, as the cell cycle proceeds, are condensedfurther to produce mitotic chromosomes. The presence of a second specializedDNA sequence, called a centromere, allows one copy of each duplicated and condensed chromosome to be pulled into each daughter cell when a cell divides.
Aprotein complex called a kinetochore forms at the centromere and attaches theduplicated chromosomes to the mitotic spindle, allowing them to be pulled apart(discussed in Chapter 17).The third specialized DNA sequence forms telomeres, the ends of a chromosome. Telomeres contain repeated nucleotide sequences that enable the ends ofchromosomes to be efficiently replicated.
Telomeres also perform another function: the repeated telomere DNA sequences, together with the regions adjoiningthem, form structures that protect the end of the chromosome from being mistaken by the cell for a broken DNA molecule in need of repair. We discuss both thistype of repair and the structure and function of telomeres in Chapter 5.In yeast cells, the three types of sequences required to propagate a chromosome are relatively short (typically less than 1000 base pairs each) and thereforeuse only a tiny fraction of the information-carrying capacity of a chromosome.Although telomere sequences are fairly simple and short in all eukaryotes, theDNA sequences that form centromeres and replication origins in more complexorganisms are much longer than their yeast counterparts. For example, experiments suggest that a human centromere can contain up to a million nucleotidepairs and that it may not require a stretch of DNA with a defined nucleotidesequence.
Instead, as we shall discuss later in this chapter, a human centromereis thought to consist of a large, regularly repeating protein–nucleic acid structurethat can be inherited when a chromosome replicates.INTERPHASEMITOSISINTERPHASEtelomerereplicationoriginCELLDIVISION+centromerereplicatedchromosomeportion ofmitotic spindleduplicatedchromosomesin separatedaughter cells1 µmFigure 4–18 A mitotic chromosome.A mitotic chromosome is a condensedduplicated chromosome in which thetwo new chromosomes, called sisterchromatids, are still linked together (seeFigure 4–17). The constricted regionindicates the position of the centromere.(Courtesy ofTerry m4.20/4.18D. Allen.)MBoC6Figure 4–19 The three DNA sequencesrequired to produce a eukaryoticchromosome that can be replicated andthen segregated accurately at mitosis.Each chromosome has multiple originsof replication, one centromere, and twotelomeres.
Shown here is the sequence ofevents that a typical chromosome followsduring the cell cycle. The DNA replicatesin interphase, beginning at the origins ofreplication and proceeding bidirectionallyfrom the origins across the chromosome.In M phase, the centromere attaches theduplicated chromosomes to the mitoticspindle so that a copy of the entire genomeis distributed to each daughter cell duringmitosis; the special structure that attachesthe centromere to the spindle is a proteincomplex called the kinetochore (darkgreen).
The centromere also helps to holdthe duplicated chromosomes togetheruntil they are ready to be moved apart.The telomeres form special caps at eachchromosome end.CHROMOSOMAL DNA AND ITS PACKAGING IN THE CHROMATIN FIBER187DNA Molecules Are Highly Condensed in ChromosomesAll eukaryotic organisms have special ways of packaging DNA into chromosomes.For example, if the 48 million nucleotide pairs of DNA in human chromosome22 could be laid out as one long perfect double helix, the molecule would extendfor about 1.5 cm if stretched out end to end. But chromosome 22 measures onlyabout 2 μm in length in mitosis (see Figures 4–10 and 4–11), representing an endto-end compaction ratio of over 7000-fold.
This remarkable feat of compressionis performed by proteins that successively coil and fold the DNA into higher andhigher levels of organization. Although much less condensed than mitotic chromosomes, the DNA of human interphase chromosomes is still tightly packed.In reading these sections it is important to keep in mind that chromosomestructure is dynamic. We have seen that each chromosome condenses to anextreme degree in the M phase of the cell cycle. Much less visible, but of enormousinterest and importance, specific regions of interphase chromosomes decondense to allow access to specific DNA sequences for gene expression, DNA repair,and replication—and then recondense when these processes are completed.
Thepackaging of chromosomes is therefore accomplished in a way that allows rapidlocalized, on-demand access to the DNA. In the next sections, we discuss the specialized proteins that make this type of packaging possible.Nucleosomes Are a Basic Unit of Eukaryotic ChromosomeStructureThe proteins that bind to the DNA to form eukaryotic chromosomes are traditionally divided into two classes: the histones and the non-histone chromosomalproteins, each contributing about the same mass to a chromosome as the DNA.The complex of both classes of protein with the nuclear DNA of eukaryotic cells isknown as chromatin (Figure 4–20).Histones are responsible for the first and most basic level of chromosomepacking, the nucleosome, a protein–DNA complex discovered in 1974.
Wheninterphase nuclei are broken open very gently and their contents examined underthe electron microscope, most of the chromatin appears to be in the form of afiber with a diameter of about 30 nm (Figure 4–21A). If this chromatin is subjected to treatments that cause it to unfold partially, it can be seen under the electron microscope as a series of “beads on a string” (Figure 4–21B). The string isDNA, and each bead is a “nucleosome core particle” that consists of DNA woundaround a histone core (Movie 4.2).The structural organization of nucleosomes was determined after first isolating them from unfolded chromatin by digestion with particular enzymes (callednucleases) that break down DNA by cutting between the nucleosomes.
Afterdigestion for a short period, the exposed DNA between the nucleosome core particles, the linker DNA, is degraded. Each individual nucleosome core particle consists of a complex of eight histone proteins—two molecules each of histones H2A,chromatinDNAhistonenon-histone proteinsFigure 4–20 Chromatin.
As illustrated,chromatin consists of DNA bound to bothhistone and non-histone proteins. Themass of histone protein present is aboutequal to the total mass of non-histoneprotein, but—as schematically indicatedhere—the latter class is composed of anenormous number of different species. Intotal, a chromosome is about one-thirdDNA and two-thirds protein by mass.Chapter 4: DNA, Chromosomes, and Genomes188Figure 4–21 Nucleosomes as seen inthe electron microscope.
(A) Chromatinisolated directly from an interphase nucleusappears in the electron microscope as athread about 30 nm thick. (B) This electronmicrograph shows a length of chromatinthat has been experimentally unpacked,or decondensed, after isolation to showthe nucleosomes. (A, courtesy of BarbaraHamkalo; B, courtesy of Victoria Foe.)(A)(B)50 nmH2B, H3, and H4—and double-stranded DNA that is 147 nucleotide pairs long.The histone octamer forms a protein core around which the double-stranded DNAis wound (Figure 4–22).The region of linker DNA that separates each nucleosome core particle fromMBoC6m4.22/4.20the next can vary in length froma fewnucleotide pairs up to about 80. (The termnucleosome technically refers to a nucleosome core particle plus one of its adjacentDNA linkers, but it is often used synonymously with nucleosome core particle.)On average, therefore, nucleosomes repeat at intervals of about 200 nucleotidepairs.
For example, a diploid human cell with 6.4 × 109 nucleotide pairs containsapproximately 30 million nucleosomes. The formation of nucleosomes converts aDNA molecule into a chromatin thread about one-third of its initial length.The Structure of the Nucleosome Core Particle Reveals How DNAIs PackagedThe high-resolution structure of a nucleosome core particle, solved in 1997,revealed a disc-shaped histone core around which the DNA was tightly wrappedin a left-handed coil of 1.7 turns (Figure 4–23).
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