B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 75
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(A) The structure of the nucleosome highlighting the location ofthe first 30 amino acids in each of its eight N-terminal histone tails (green). These tails are unstructured and highly mobile, andthus will change their conformation depending on other bound proteins. (B) Well-documented modifications of the four histonecore proteins are indicated. Although only a single symbol is used here for methylation (M), each lysine (K) or arginine (R) can bemethylated in several different ways. Note also that some positions (e.g., lysine 9 of H3) can be modified either by methylationor by acetylation, but not both. Most of the modifications shown add a relatively small molecule onto the histone tails; theexception is ubiquitin, a 76-amino-acid protein also used for other cell processes (see Figure 3–69).
Not shown are more than20 possible modifications located in the globular core of the histones. (A, PDB: 1KX5; B, adapted from H. Santos-Rosa andC. Caldas, Eur. J. Cancer 41:2381–2402, 2005. With permission from Elsevier.)different times and places in the life of an organism, thereby determining whereand when the chromatin-modifying enzymes will act. In this way, the DNAsequence ultimately determines how histones are modified. But in at least somem4.39/4.32cases, the covalent modifications on nucleosomesMBoC6can persistlong after the transcription regulator proteins that first induced them have disappeared, therebyproviding the cell with a memory of its developmental history.
Most remarkably,as in the related phenomenon of position effect variegation discussed above, thismemory can be transmitted from one cell generation to the next.Very different patterns of covalent modification are found on different groupsof nucleosomes, depending both on their exact position in the genome and onthe history of the cell. The modifications of the histones are carefully controlled,and they have important consequences. The acetylation of lysines on the N-terminal tails loosens chromatin structure, in part because adding an acetyl groupto lysine removes its positive charge, thereby reducing the affinity of the tails foradjacent nucleosomes. However, the most profound effects of the histone modifications lie in their ability to recruit specific other proteins to the modified stretchof chromatin.
Trimethylation of one specific lysine on the histone H3 tail, forinstance, attracts the heterochromatin-specific protein HP1 and contributes tothe establishment and spread of heterochromatin. More generally, the recruitedproteins act with the modified histones to determine how and when genes will beexpressed, as well as other chromosome functions. In this way, the precise structure of each domain of chromatin governs the readout of the genetic informationthat it contains, and thereby the structure and function of the eukaryotic cell.198Chapter 4: DNA, Chromosomes, and Genomeshistone foldSPECIAL FUNCTIONH3H3.3transcriptional activationCENP-Aloop insertcentromere function andkinetochore assemblyH2AH2AXDNA repair andrecombinationH2AZgene expression,chromosome segregationmacroH2Atranscriptional repression,X-chromosome inactivationhistone foldChromatin Acquires Additional Variety Through the Site-SpecificInsertion of a Small Set of Histone VariantsIn addition to the four highly conserved standard core histones, eukaryotes alsoMBoC6 m4.41/4.33contain a few variant histonesthat can also assemble into nucleosomes.
Thesehistones are present in much smaller amounts than the major histones, and theyhave been less well conserved over long evolutionary times. Variants are knownfor each of the core histones with the exception of H4; some examples are shownin Figure 4–35.The major histones are synthesized primarily during the S phase of the cellcycle and assembled into nucleosomes on the daughter DNA helices just behindthe replication fork (see Figure 5–32). In contrast, most histone variants are synthesized throughout interphase. They are often inserted into already-formedchromatin, which requires a histone-exchange process catalyzed by the ATP-dependent chromatin remodeling complexes discussed previously.
These remodeling complexes contain subunits that cause them to bind both to specific sites onchromatin and to histone chaperones that carry a particular variant. As a result,each histone variant is inserted into chromatin in a highly selective manner (seeFigure 4–27).Covalent Modifications and Histone Variants Act in Concert toControl Chromosome FunctionsThe number of possible distinct markings on an individual nucleosome is in principle enormous, and this potential for diversity is still greater when we allow fornucleosomes that contain histone variants. However, the histone modificationsare known to occur in coordinated sets.
More than 15 such sets can be identifiedin mammalian cells. However, it is not yet clear how many different types of chromatin are functionally important in cells.Some combinations are known to have a specific meaning for the cell in thesense that they determine how and when the DNA packaged in the nucleosomesis to be accessed or manipulated—a fact that led to the idea of a “histone code.”For example, one type of marking signals that a stretch of chromatin has beennewly replicated, another signals that the DNA in that chromatin has been damaged and needs repair, while others signal when and how gene expression shouldtake place.
Various regulatory proteins contain small domains that bind to specific marks, recognizing, for example, a trimethylated lysine 4 on histone H3 (Figure 4–36). These domains are often linked together as modules in a single largeFigure 4–35 The structure of some histonevariants compared with the major histonethat they replace. The histone variantsare inserted into nucleosomes at specificsites on chromosomes by ATP-dependentchromatin remodeling enzymes that act inconcert with histone chaperones (see Figure4–27). The CENP-A (Centromere Protein-A)variant of histone H3 is discussed later inthis chapter (see Figure 4–42); other variantsare discussed in Chapter 7.
The sequencesin each variant that are colored differently(compared to the major histone above it)denote regions with an amino acid sequencedifferent from this major histone. (Adaptedfrom K. Sarma and D. Reinberg, Nat. Rev.Mol. Cell Biol. 6:139–149, 2005. Withpermission from Macmillan Publishers Ltd.)CHROMATIN STRUCTURE AND FUNCTION199CH3CH3H3CNZn+Zn(A)Arg2Lys4Thr6Thr3N-terminusAlaGln5(B)(C)Figure 4–36 How a mark on a nucleosome is read. The figure shows the structure of a protein module (called an ING PHDdomain) that specifically recognizes histone H3 trimethylated on lysine 4.
(A) A trimethyl group. (B) Space-filling model of an INGPHD domain bound to a histone tail (green, with the trimethyl group highlighted in yellow). (C) A ribbon model showing howthe N-terminal six amino acids in the H3 tail are recognized. The red lines represent hydrogen bonds. This is one of a family ofPHD domains that recognize methylated lysines on histones; different members of the family bind tightly to lysines located atdifferent positions, and they can discriminate between a mono-, di-, and trimethylated lysine. In a similar way, other small proteinmodules recognize specific histone side chains that have been marked with acetyl groups, phosphate groups, and so on.(Adapted from P.V. Peña et al., Nature 442:100–103, 2006.
With permission from Macmillan Publishers Ltd.)protein or protein complex, which thereby recognizes a specific combination ofMBoC6 m4.42/4.34histone modifications (Figure 4–37). The resultis a reader complex that allowsparticular combinations of markings on chromatin to attract additional proteins,so as to execute an appropriate biological function at the right time (Figure 4–38).The marks on nucleosomes due to covalent additions to histones are dynamic,being constantly removed and added at rates that depend on their chromosomallocations. Because the histone tails extend outward from the nucleosome coreand are likely to be accessible even when chromatin is condensed, they wouldseem to provide an especially suitable format for creating marks that can bereadily altered as a cell’s needs change.
Although much remains to be learnedabout the meaning of the different histone modifications, a few well-studiedexamples of the information that can be encoded in the histone H3 tail are listedin Figure 4–39.A Complex of Reader and Writer Proteins Can Spread SpecificChromatin Modifications Along a ChromosomeThe phenomenon of position effect variegation described previously requires thatsome modified forms of chromatin have the ability to spread for substantial distances along a chromosomal DNA molecule (see Figure 4–31). How is this possible?The enzymes that add or remove modifications to histones in nucleosomesare part of multisubunit complexes.
They can initially be brought to a particular region of chromatin by one of the sequence-specific DNA-binding proteins(transcription regulators) discussed in Chapters 6 and 7 (for a specific example,Figure 4–37 Recognition of a specific combination of marks on anucleosome. In the example shown, two adjacent domains that are part ofthe NURF (Nucleosome Remodeling Factor) chromatin remodeling complexbind to the nucleosome, with the PHD domain (red) recognizing a methylatedH3 lysine 4 and another domain (a bromodomain, blue) recognizing anacetylated H4 lysine 16.
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