B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 77
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(Based onA.G. West and P. Fraser, Hum. Mol. Genet.14:R101–R111, 2005. With permissionfrom Oxford University Press.)CHROMATIN STRUCTURE AND FUNCTIONnormalnucleosome(A)203nucleosome withcentromere-specifichistone H3sequence-specificDNA-binding proteinyeast centromeric DNAmicrotubuleyeast kinetochore(B)centromerespecificnucleosomeThe Chromatin in Centromeres Reveals How Histone Variants CanCreate Special StructuresNucleosomes carrying histone variants have a distinctive character and arethought to be able to produce marks in chromatin that are unusually long-lasting.An important example is seen in the formation and inheritance of the specializedchromatin structure at the centromere, the region of each chromosome requiredfor attachment to the mitotic spindle and orderly segregation of the duplicatedcopies of the genome into daughter cells each time a cell divides.
In many complex organisms, including humans, each centromere is embedded in a stretch ofspecial centromeric chromatin that persists throughout interphase, even thoughthe centromere-mediated attachment to the spindle and movement of DNA occurMBoC6m4.48/4.41only during mitosis. Thischromatincontains a centromere-specific variant H3histone, known as CENP-A (Centromere Protein-A; see Figure 4–35), plus additional proteins that pack the nucleosomes into particularly dense arrangementsand form the kinetochore, the special structure required for attachment of themitotic spindle (see Figure 4–19).A specific DNA sequence of approximately 125 nucleotide pairs is sufficient toserve as a centromere in the yeast S. cerevisiae.
Despite its small size, more thana dozen different proteins assemble on this DNA sequence; the proteins includethe CENP-A histone H3 variant, which, along with the three other core histones,forms a centromere-specific nucleosome. The additional proteins at the yeastcentromere attach this nucleosome to a single microtubule from the yeast mitoticspindle (Figure 4–42).The centromeres in more complex organisms are considerably larger thanthose in budding yeasts. For example, fly and human centromeres extend overhundreds of thousands of nucleotide pairs and, while they contain CENP-A, theydo not seem to contain a centromere-specific DNA sequence.
These centromereslargely consist of short, repeated DNA sequences, known as alpha satellite DNAin humans. But the same repeat sequences are also found at other (non-centromeric) positions on chromosomes, indicating that they are not sufficient to directcentromere formation. Most strikingly, in some unusual cases, new human centromeres (called neocentromeres) have been observed to form spontaneously onfragmented chromosomes. Some of these new positions were originally euchromatic and lack alpha satellite DNA altogether (Figure 4–43). It seems that centromeres in complex organisms are defined by an assembly of proteins, ratherthan by a specific DNA sequence.Inactivation of some centromeres and genesis of others de novo seem to haveplayed an essential part in evolution.
Different species, even when quite closelyFigure 4–42 A model for the structureof a simple centromere. (A) In the yeastSaccharomyces cerevisiae, a specialcentromeric DNA sequence assembles asingle nucleosome in which two copies ofan H3 variant histone (called CENP-A inmost organisms) replace the normal H3.(B) How peptide sequences unique tothis variant histone (see Figure 4–35) helpto assemble additional proteins, someof which form a kinetochore. The yeastkinetochore is unusual in capturing onlya single microtubule; humans have muchlarger centromeres and form kinetochoresthat can capture 20 or more microtubules(see Figure 4–43).
The kinetochore isdiscussed in detail in Chapter 17. (Adaptedfrom A. Joglekar et al., Nat. Cell Biol.8:581–585, 2006. With permission fromMacmillan Publishers Ltd.)204Chapter 4: DNA, Chromosomes, and Genomeshigher-order repeatalpha satellite DNA monomer(171 nucleotide pairs)active centromere(A)pericentricheterochromatininactive centromerewith nonfunctionalalpha satellite DNA(B)neocentromere formedwithout alpha satellite DNAFigure 4–43 Evidence for the plasticity of human centromere formation.
(A) A series of A-T-rich alpha satellite DNAsequences is repeated many thousands of times at each human centromere (red), and is surrounded by pericentricheterochromatin (brown). However, due to an ancient chromosome breakage-and-rejoining event, some human chromosomescontain two blocks of alpha satellite DNA, each of which presumably functioned as a centromere in its original chromosome.Usually, chromosomes with two functional centromeres are not stably propagated because they attach improperly to thespindle and are broken apart during mitosis. In chromosomes that do survive, however, one of the centromeres has somehowbecome inactivated, even though it contains all the necessary DNA sequences.
This allows the chromosome to be stablypropagated. (B) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring. Some ofthese extra chromosomes, which have formed from a breakage event, lack alpha satellite DNA altogether, yet new centromeres(neocentromeres) have arisen from what was originally euchromatic DNA.The complexity of centromeric chromatin is not illustrated in these diagrams. The alpha satellite DNA that forms centromericchromatin in humans is packaged into alternating blocks of chromatin.
One block is formed from a long string of nucleosomescontaining the CENP-A H3 variant histone; the other block contains nucleosomes that are specially marked with dimethyl lysine4 on the normal H3 histone. Each block is more than a thousand nucleosomes long. This centromeric chromatin is flanked bypericentric heterochromatin, as shown.
The pericentric chromatin contains methylated lysine 9 on its H3 histones, along withHP1 protein, and it is an example of “classical” heterochromatin (see Figure 4–39).related, often have different numbers of chromosomes; see Figure 4–14 for anextreme example. As we shall discuss below, detailed genome comparisons showthat in many cases the changes in chromosome numbers have arisen throughchromosome breakage-and-rejoining events, creating novel chromosomes, someof which must initially have contained abnormal numbers of centromeres—eithermore than one, or none at all. Yet stable inheritance requires that each chromosome should contain one centromere, and one only. It seems that surplus centromeres must have been inactivated, and/or new centromeres created, so as toallow the rearranged chromosome sets to be stably maintained.MBoC6 m4.49/4.42Some Chromatin Structures Can Be Directly InheritedThe changes in centromere activity just discussed, once established, need to beperpetuated through subsequent cell generations.
What could be the mechanismof this type of epigenetic inheritance?It has been proposed that de novo centromere formation requires an initialseeding event, involving the formation of a specialized DNA–protein structure thatcontains nucleosomes formed with the CENP-A variant of histone H3.
In humans,this seeding event happens more readily on arrays of alpha satellite DNA thanon other DNA sequences. The H3–H4 tetramers from each nucleosome on theparental DNA helix are directly inherited by the sister DNA helices at a replicationfork (see Figure 5–32). Therefore, once a set of CENP-A-containing nucleosomeshas been assembled on a stretch of DNA, it is easy to understand how a new centromere could be generated in the same place on both daughter chromosomesfollowing each round of cell division. One need only assume that the presence ofthe CENP-A histone in an inherited nucleosome selectively recruits more CENP-Ahistone to its newly formed neighbors.There are some striking similarities between the formation and maintenanceof centromeres and the formation and maintenance of some other regions ofCHROMATIN STRUCTURE AND FUNCTIONheterochromatin proteins205Figure 4–44 How the packaging ofDNA in chromatin can be inheritedfollowing chromosome replication.In this model, some of the specializedchromatin components are distributedto each sister chromosome after DNAduplication, along with the specially markednucleosomes that they bind.
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