Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

204 Chapter 4: DNA, Chromosomes, and Genomes
higher-order repeat
alpha satellite DNA monomer
(171 nucleotide pairs)
active centromere
(A)
pericentric
heterochromatin
inactive centromere
with nonfunctional
alpha satellite DNA
(B)
neocentromere formed
without alpha satellite DNA
Figure 4–43 Evidence for the plasticity of human centromere formation. (A) A series of A-T-rich alpha satellite DNA
sequences is repeated many thousands of times at each human centromere (red), and is surrounded by pericentric
heterochromatin (brown). However, due to an ancient chromosome breakage-and-rejoining event, some human chromosomes
contain 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 the
spindle and are broken apart during mitosis. In chromosomes that do survive, however, one of the centromeres has somehow
become inactivated, even though it contains all the necessary DNA sequences. This allows the chromosome to be stably
propagated. (B) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring. Some of
these 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 centromeric
chromatin in humans is packaged into alternating blocks of chromatin. One block is formed from a long string of nucleosomes
containing the CENP-A H3 variant histone; the other block contains nucleosomes that are specially marked with dimethyl lysine
4 on the normal H3 histone. Each block is more than a thousand nucleosomes long. This centromeric chromatin is flanked by
pericentric heterochromatin, as shown. The pericentric chromatin contains methylated lysine 9 on its H3 histones, along with
HP1 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 an
extreme example. As we shall discuss below, detailed genome comparisons show
that in many cases the changes in chromosome numbers have arisen through
chromosome breakage-and-rejoining events, creating novel chromosomes, some
of which must initially have contained abnormal numbers of centromeres—either
more 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 to
allow the rearranged chromosome sets to be stably maintained.
MBoC6 m4.49/4.42
Some Chromatin Structures Can Be Directly Inherited
The changes in centromere activity just discussed, once established, need to be
perpetuated through subsequent cell generations. What could be the mechanism
of this type of epigenetic inheritance?
It has been proposed that de novo centromere formation requires an initial
seeding event, involving the formation of a specialized DNA–protein structure that
contains nucleosomes formed with the CENP-A variant of histone H3. In humans,
this seeding event happens more readily on arrays of alpha satellite DNA than
on other DNA sequences. The H3–H4 tetramers from each nucleosome on the
parental DNA helix are directly inherited by the sister DNA helices at a replication
fork (see Figure 5–32). Therefore, once a set of CENP-A-containing nucleosomes
has 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 chromosomes
following each round of cell division. One need only assume that the presence of
the CENP-A histone in an inherited nucleosome selectively recruits more CENP-A
histone to its newly formed neighbors.
There are some striking similarities between the formation and maintenance
of centromeres and the formation and maintenance of some other regions of