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

198 Chapter 4: DNA, Chromosomes, and Genomes
H3
H3.3
CENP-A
H2A
H2AX
H2AZ
loop insert
histone fold
SPECIAL FUNCTION
transcriptional activation
centromere function and
kinetochore assembly
DNA repair and
recombination
gene expression,
chromosome segregation
Figure 4–35 The structure of some histone
variants compared with the major histone
that they replace. The histone variants
are inserted into nucleosomes at specific
sites on chromosomes by ATP-dependent
chromatin remodeling enzymes that act in
concert with histone chaperones (see Figure
4–27). The CENP-A (Centromere Protein-A)
variant of histone H3 is discussed later in
this chapter (see Figure 4–42); other variants
are discussed in Chapter 7. The sequences
in each variant that are colored differently
(compared to the major histone above it)
denote regions with an amino acid sequence
different from this major histone. (Adapted
from K. Sarma and D. Reinberg, Nat. Rev.
Mol. Cell Biol. 6:139–149, 2005. With
permission from Macmillan Publishers Ltd.)
macroH2A
transcriptional repression,
X-chromosome inactivation
histone fold
Chromatin Acquires Additional Variety Through the Site-Specific
Insertion of a Small Set of Histone Variants
In addition to the four highly conserved standard core histones, eukaryotes also
MBoC6 m4.41/4.33
contain a few variant histones that can also assemble into nucleosomes. These
histones are present in much smaller amounts than the major histones, and they
have been less well conserved over long evolutionary times. Variants are known
for each of the core histones with the exception of H4; some examples are shown
in Figure 4–35.
The major histones are synthesized primarily during the S phase of the cell
cycle and assembled into nucleosomes on the daughter DNA helices just behind
the replication fork (see Figure 5–32). In contrast, most histone variants are synthesized
throughout interphase. They are often inserted into already-formed
chromatin, 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 on
chromatin and to histone chaperones that carry a particular variant. As a result,
each histone variant is inserted into chromatin in a highly selective manner (see
Figure 4–27).
Covalent Modifications and Histone Variants Act in Concert to
Control Chromosome Functions
The number of possible distinct markings on an individual nucleosome is in principle
enormous, and this potential for diversity is still greater when we allow for
nucleosomes that contain histone variants. However, the histone modifications
are known to occur in coordinated sets. More than 15 such sets can be identified
in 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 the
sense that they determine how and when the DNA packaged in the nucleosomes
is 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 been
newly replicated, another signals that the DNA in that chromatin has been damaged
and needs repair, while others signal when and how gene expression should
take 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 large