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

190 Chapter 4: DNA, Chromosomes, and Genomes
core. The bending requires a substantial compression of the minor groove of the
DNA helix. Certain dinucleotides in the minor groove are especially easy to compress,
and some nucleotide sequences bind the nucleosome more tightly than
others (Figure 4–25). This probably explains some striking, but unusual, cases
of very precise positioning of nucleosomes along a stretch of DNA. However, the
sequence preference of nucleosomes must be weak enough to allow other factors
to dominate, inasmuch as nucleosomes can occupy any one of a number of positions
relative to the DNA sequence in most chromosomal regions.
In addition to its histone fold, each of the core histones has an N-terminal
amino acid “tail,” which extends out from the DNA–histone core (see Figure
4–24D). These histone tails are subject to several different types of covalent modifications
that in turn control critical aspects of chromatin structure and function,
as we shall discuss shortly.
As a reflection of their fundamental role in DNA function through controlling
chromatin structure, the histones are among the most highly conserved eukaryotic
proteins. For example, the amino acid sequence of histone H4 from a pea
differs from that of a cow at only 2 of the 102 positions. This strong evolutionary
conservation suggests that the functions of histones involve nearly all of their
amino acids, so that a change in any position is deleterious to the cell. But in addition
to this remarkable conservation, eukaryotic organisms also produce smaller
amounts of specialized variant core histones that differ in amino acid sequence
from the main ones. As discussed later, these variants, combined with the surprisingly
large number of covalent modifications that can be added to the histones in
nucleosomes, give rise to a variety of chromatin structures in cells.
Nucleosomes Have a Dynamic Structure, and Are Frequently
Subjected to Changes Catalyzed by ATP-Dependent Chromatin
Remodeling Complexes
For many years biologists thought that, once formed in a particular position on
DNA, a nucleosome would remain fixed in place because of the very tight association
between its core histones and DNA. If true, this would pose problems for
genetic readout mechanisms, which in principle require easy access to many
specific DNA sequences. It would also hinder the rapid passage of the DNA transcription
and replication machinery through chromatin. But kinetic experiments
show that the DNA in an isolated nucleosome unwraps from each end at a rate of
about four times per second, remaining exposed for 10 to 50 milliseconds before
the partially unwrapped structure recloses. Thus, most of the DNA in an isolated
nucleosome is in principle available for binding other proteins.
For the chromatin in a cell, a further loosening of DNA–histone contacts is
clearly required, because eukaryotic cells contain a large variety of ATP-dependent
chromatin remodeling complexes. These complexes include a subunit that
hydrolyzes ATP (an ATPase evolutionarily related to the DNA helicases discussed
in Chapter 5). This subunit binds both to the protein core of the nucleosome and
to the double-stranded DNA that winds around it. By using the energy of ATP
hydrolysis to move this DNA relative to the core, the protein complex changes the
structure of a nucleosome temporarily, making the DNA less tightly bound to the
histone core. Through repeated cycles of ATP hydrolysis that pull the nucleosome
core along the DNA double helix, the remodeling complexes can catalyze nucleosome
sliding. In this way, they can reposition nucleosomes to expose specific
regions of DNA, thereby making them available to other proteins in the cell (Figure
4–26). In addition, by cooperating with a variety of other proteins that bind to
histones and serve as histone chaperones, some remodeling complexes are able to
remove either all or part of the nucleosome core from a nucleosome—catalyzing
either an exchange of its H2A–H2B histones, or the complete removal of the octameric
core from the DNA (Figure 4–27). As a result of such processes, measurements
reveal that a typical nucleosome is replaced on the DNA every one or two
hours inside the cell.
AA, TT, and TA dinucleotides
preferred here
(minor groove inside)
histone core
of nucleosome
(histone octamer)
G-C preferred here
(minor groove outside)
MBoC6 m4.27/4.24
DNA of
nucleosome
Figure 4–25 The bending of DNA in a
nucleosome. The DNA helix makes
1.7 tight turns around the histone octamer.
This diagram illustrates how the minor
groove is compressed on the inside of the
turn. Owing to structural features of the
DNA molecule, the indicated dinucleotides
are preferentially accommodated in such
a narrow minor groove, which helps to
explain why certain DNA sequences
will bind more tightly than others to the
nucleosome core.