B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 73
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Eachcycle of ATP binding, ATP hydrolysis, andrelease of the ADP and Pi products therebymoves the DNA with respect to the histoneoctamer in the direction of the arrow in thisdiagram. It requires many such cycles toproduce the nucleosome sliding shown.(B) The structure of a nucleosome-bounddimer of the two identical ATPase subunits(green) that slide nucleosomes back andforth in the ISW1 family of chromatinremodeling complexes. (C) The structureof a large chromatin remodeling complex,showing how it is thought to wrap around anucleosome.
Modeled in green is the yeastRSC complex, which contains 15 subunits—including an ATPase and at least foursubunits with domains that recognize specificcovalently modified histones. (B, fromL.R. Racki et al., Nature 462:1016–1021,2009. With permission from MacmillanPublishers Ltd; C, adapted fromA.E.
Leschziner et al., Proc. Natl Acad. Sci.USA 104:4913–4918, 2007.)192Chapter 4: DNA, Chromosomes, and GenomesFigure 4–27 Nucleosome removal and histoneexchange catalyzed by ATP-dependent chromatinremodeling complexes. By cooperating with specificmembers of a large family of different histone chaperones,some chromatin remodeling complexes can removethe H2A–H2B dimers from a nucleosome (top series ofreactions) and replace them with dimers that contain avariant histone, such as the H2AZ–H2B dimer (see Figure4–35). Other remodeling complexes are attracted tospecific sites on chromatin and cooperate with histonechaperones to remove the histone octamer completelyand/or to replace it with a different nucleosome core(bottom series of reactions).
Highly simplified views of theprocesses are illustrated here.histone chaperoneATP-dependentchromatinremodelingcomplexATPATPADPEXCHANGE OFH2A–H2B DIMERSADPATPADPEXCHANGE OFNUCLEOSOME CORE(HISTONE OCTAMER)DNA lackingnucleosomehistonechaperoneHow nucleosomes are organized into condensed arrays is unclear. The structure of a tetranucleosome (a complex of four nucleosomes) obtained by x-raycrystallography and high-resolution electron microscopy of reconstituted chromatin have been used to support a zigzag model for the stacking of nucleosomesin a 30-nm fiber (Figure 4–28). But cryoelectron microscopy of carefully preparednuclei suggests that most regions of chromatin are less regularly structured.What causes nucleosomes to stack so tightly on each other? Nucleosome-tonucleosome linkages that involve histone tails, most notably the H4 tail, constitute one important factor (Figure 4–29).
Another important factor is an additionalMBoC6 m4.30/4.26histone that is often present in a 1-to-1 ratio with nucleosome cores, known ashistone H1. This so-called linker histone is larger than the individual core histonesand it has been considerably less well conserved during evolution. A single histone H1 molecule binds to each nucleosome, contacting both DNA and protein,and changing the path of the DNA as it exits from the nucleosome.
This change inthe exit path of DNA is thought to help compact nucleosomal DNA (Figure 4–30).(B)(A)(C)Figure 4–28 A zigzag model for the 30nm chromatin fiber. (A) The conformationof two of the four nucleosomes in atetranucleosome, from a structuredetermined by x-ray crystallography.(B) Schematic of the entire tetranucleosome;the fourth nucleosome is not visible, beingstacked on the bottom nucleosome andbehind it in this diagram. (C) Diagrammaticillustration of a possible zigzag structurethat could account for the 30-nm chromatinfiber.
(A, PDB code: 1ZBB; C, adaptedfrom C.L. Woodcock, Nat. Struct. Mol. Biol.12:639–640, 2005. With permission fromMacmillan Publishers Ltd.)CHROMOSOMAL DNA AND ITS PACKAGING IN THE CHROMATIN FIBERH4 tail193H2B tailH3 tailH2A tailH2A tailH4 tailH2B tailH3 tail(A)(B)Most eukaryotic organisms make several histone H1 proteins of related but quitedistinct amino acid sequences. The presence of many other DNA-binding proteins, as well as proteins that bind directly to histones, is certain to add importantadditional features to any array of nucleosomes.MBoC6 m4.33/4.27.5SummaryA gene is a nucleotide sequence in a DNA molecule that acts as a functional unitfor the production of a protein, a structural RNA, or a catalytic or regulatory RNAmolecule. In eukaryotes, protein-coding genes are usually composed of a string ofalternating introns and exons associated with regulatory regions of DNA.
A chromosome is formed from a single, enormously long DNA molecule that contains alinear array of many genes, bound to a large set of proteins. The human genomecontains 3.2 × 109 DNA nucleotide pairs, divided between 22 different autosomes(present in two copies each) and 2 sex chromosomes. Only a small percentage of thisDNA codes for proteins or functional RNA molecules. A chromosomal DNA molecule also contains three other types of important nucleotide sequences: replicationorigins and telomeres allow the DNA molecule to be efficiently replicated, while acentromere attaches the sister DNA molecules to the mitotic spindle, ensuring theiraccurate segregation to daughter cells during the M phase of the cell cycle.The DNA in eukaryotes is tightly bound to an equal mass of histones, whichform repeated arrays of DNA–protein particles called nucleosomes.
The nucleosomeis composed of an octameric core of histone proteins around which the DNA double helix is wrapped. Nucleosomes are spaced at intervals of about 200 nucleotidepairs, and they are usually packed together (with the aid of histone H1 molecules)into quasi-regular arrays to form a 30-nm chromatin fiber. Even though compact,the structure of chromatin must be highly dynamic to allow access to the DNA.There is some spontaneous DNA unwrapping and rewrapping in the nucleosomeitself; however, the general strategy for reversibly changing local chromatin structure features ATP-driven chromatin remodeling complexes. Cells contain a large setof such complexes, which are targeted to specific regions of chromatin at appropriate times.
The remodeling complexes collaborate with histone chaperones to allownucleosome cores to be repositioned, reconstituted with different histones, or completely removed to expose the underlying DNA.Figure 4–29 A model for the role playedby histone tails in the compaction ofchromatin. (A) A schematic diagramshows the approximate exit points ofthe eight histone tails, one from eachhistone protein, that extend from eachnucleosome. The actual structure isshown to its right. In the high-resolutionstructure of the nucleosome, the tails arelargely unstructured, suggesting that theyare highly flexible. (B) As indicated, thehistone tails are thought to be involved ininteractions between nucleosomes thathelp to pack them together.
(A, PDBcode: 1K X 5.)histone H1nucleosomeC(A)Nhistone H1(B)(C)Figure 4–30 How the linker histonebinds to the nucleosome. The positionand structure of histone H1 is shown. TheH1 core region constrains an additional20 nucleotide pairs of DNA where it exitsfrom the nucleosome core and is importantfor compacting chromatin. (A) Schematic,and (B) structure inferred for a singlenucleosome from a structure determinedby high-resolution electron microscopy ofa reconstituted chromatin fiber (C).
(B andC, adapted from F. Song et al., Science344:376–380, 2014.)194Chapter 4: DNA, Chromosomes, and GenomesCHROMATIN STRUCTURE AND FUNCTIONHaving described how DNA is packaged into nucleosomes to create a chromatinfiber, we now turn to the mechanisms that create different chromatin structuresin different regions of a cell’s genome. Mechanisms of this type have a variety ofimportant functions in cells. Most strikingly, certain types of chromatin structurecan be inherited; that is, the structure can be directly passed down from a cellto its descendants.
Because the cell memory that results is based on an inherited chromatin structure rather than on a change in DNA sequence, this is a formof epigenetic inheritance. The prefix epi is Greek for “on”; this is appropriate,because epigenetics represents a form of inheritance that is superimposed on thegenetic inheritance based on DNA.In Chapter 7, we shall introduce the many different ways in which the expression of genes is regulated. There we discuss epigenetic inheritance in detail andpresent several different mechanisms that can produce it.
Here, we are concerned with only one, that based on chromatin structure. We begin this section byreviewing the observations that first demonstrated that chromatin structures canbe inherited. We then describe some of the chemistry that makes this possible—the covalent modification of histones in nucleosomes. These modifications havemany functions, inasmuch as they serve as recognition sites for protein domainsthat link specific protein complexes to different regions of chromatin.
Histonesthereby have effects on gene expression, as well as on many other DNA-linkedprocesses. Through such mechanisms, chromatin structure plays an importantrole in the development, growth, and maintenance of all eukaryotic organisms,including ourselves.Heterochromatin Is Highly Organized and Restricts GeneExpressionLight-microscope studies in the 1930s distinguished two types of chromatin inthe interphase nuclei of many higher eukaryotic cells: a highly condensed form,called heterochromatin, and all the rest, which is less condensed, called euchromatin.
Heterochromatin represents an especially compact form of chromatin(see Figure 4–9), and we are finally beginning to understand its molecular properties. It is highly concentrated in certain specialized regions, most notably at thecentromeres and telomeres introduced previously (see Figure 4–19), but it is alsopresent at many other locations along chromosomes—locations that can varyaccording to the physiological state of the cell.
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