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

CHROMATIN STRUCTURE AND FUNCTION
203
normal
nucleosome
(A)
(B)
microtubule
nucleosome with
centromere-specific
histone H3
yeast kinetochore
sequence-specific
DNA-binding protein
centromerespecific
nucleosome
yeast centromeric DNA
Figure 4–42 A model for the structure
of a simple centromere. (A) In the yeast
Saccharomyces cerevisiae, a special
centromeric DNA sequence assembles a
single nucleosome in which two copies of
an H3 variant histone (called CENP-A in
most organisms) replace the normal H3.
(B) How peptide sequences unique to
this variant histone (see Figure 4–35) help
to assemble additional proteins, some
of which form a kinetochore. The yeast
kinetochore is unusual in capturing only
a single microtubule; humans have much
larger centromeres and form kinetochores
that can capture 20 or more microtubules
(see Figure 4–43). The kinetochore is
discussed in detail in Chapter 17. (Adapted
from A. Joglekar et al., Nat. Cell Biol.
8:581–585, 2006. With permission from
Macmillan Publishers Ltd.)
The Chromatin in Centromeres Reveals How Histone Variants Can
Create Special Structures
Nucleosomes carrying histone variants have a distinctive character and are
thought 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 specialized
chromatin structure at the centromere, the region of each chromosome required
for attachment to the mitotic spindle and orderly segregation of the duplicated
copies of the genome into daughter cells each time a cell divides. In many complex
organisms, including humans, each centromere is embedded in a stretch of
special centromeric chromatin that persists throughout interphase, even though
the centromere-mediated attachment to the spindle and movement of DNA occur
only during mitosis. This MBoC6 chromatin m4.48/4.41 contains a centromere-specific variant H3
histone, known as CENP-A (Centromere Protein-A; see Figure 4–35), plus additional
proteins that pack the nucleosomes into particularly dense arrangements
and form the kinetochore, the special structure required for attachment of the
mitotic spindle (see Figure 4–19).
A specific DNA sequence of approximately 125 nucleotide pairs is sufficient to
serve as a centromere in the yeast S. cerevisiae. Despite its small size, more than
a dozen different proteins assemble on this DNA sequence; the proteins include
the CENP-A histone H3 variant, which, along with the three other core histones,
forms a centromere-specific nucleosome. The additional proteins at the yeast
centromere attach this nucleosome to a single microtubule from the yeast mitotic
spindle (Figure 4–42).
The centromeres in more complex organisms are considerably larger than
those in budding yeasts. For example, fly and human centromeres extend over
hundreds of thousands of nucleotide pairs and, while they contain CENP-A, they
do not seem to contain a centromere-specific DNA sequence. These centromeres
largely consist of short, repeated DNA sequences, known as alpha satellite DNA
in humans. But the same repeat sequences are also found at other (non-centromeric)
positions on chromosomes, indicating that they are not sufficient to direct
centromere formation. Most strikingly, in some unusual cases, new human centromeres
(called neocentromeres) have been observed to form spontaneously on
fragmented 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, rather
than by a specific DNA sequence.
Inactivation of some centromeres and genesis of others de novo seem to have
played an essential part in evolution. Different species, even when quite closely