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

196 Chapter 4: DNA, Chromosomes, and Genomes
(A) LYSINE ACETYLATION AND METHYLATION ARE COMPETING REACTIONS
H
O
H
O
H
O
H
O
H
O
N
C
C
N
C
C
N
C
C
N
C
C
N
C
C
H
CH 2
H
CH 2
H
CH 2
H
CH 2
H
CH 2
CH 2
CH 2
CH 2
CH 2
H
CH 2
CH 2
CH 2
CH 2
CH 2
CH 2
CH 2
CH 2
CH 2
CH 2 CH 2
+
N
NH 3 N +
N +
N +
H C O
H 3 C H
H 3 C CH 3
H 3 C CH 3
lysine
H
H
CH 3
CH 3
acetyl lysine monomethyl lysine dimethyl lysine trimethyl lysine
Figure 4–33 Some prominent types of covalent amino acid side-chain
modifications found on nucleosomal histones. (A) Three different levels
of lysine methylation are shown; each can be recognized by a different
binding protein and thus each can have a different significance for the cell.
Note that acetylation removes the plus charge on lysine, and that, most
importantly, an acetylated lysine cannot be methylated, and vice versa.
(B) Serine phosphorylation adds a negative charge to a histone. Modifications
of histones not shown here include the mono- or dimethylation of an arginine,
the phosphorylation of a threonine, the addition of ADP-ribose to a glutamic
acid, and the addition of a ubiquityl, sumoyl, or biotin group to a lysine.
As a first step, one can carry out a search for the molecules that are involved.
This has been done by means of genetic screens, in which large numbers of
mutants are generated, after which one picks out those that show an abnormality
of the process in question. Extensive genetic screens in Drosophila, fungi, and
mice have identified more than 100 genes whose products either enhance or suppress
the spread of heterochromatin and its stable inheritance—in other words,
genes that serve as either enhancers or suppressors of position effect variegation.
Many of these genes turn out to code for non-histone chromosomal proteins that
interact with histones and are involved in modifying or maintaining chromatin
structure. We shall discuss how they work in the sections that follow.
(B) SERINE PHOSPHORYLATION
H O
O
N C C
N C C
H CH 2
H CH 2
OH
O
serine
O P O
O _
phosphoserine
The Core Histones Are Covalently Modified MBoC6 at Many m4.38/4.31 Different Sites
The amino acid side chains of the four histones in the nucleosome core are subjected
to a remarkable variety of covalent modifications, including the acetylation
of lysines, the mono-, di-, and trimethylation of lysines, and the phosphorylation
of serines (Figure 4–33). A large number of these side-chain modifications occur
on the eight relatively unstructured N-terminal “histone tails” that protrude from
the nucleosome (Figure 4–34). However, there are also more than 20 specific sidechain
modifications on the nucleosome’s globular core.
All of the above types of modifications are reversible, with one enzyme serving
to create a particular type of modification, and another to remove it. These
enzymes are highly specific. Thus, for example, acetyl groups are added to specific
lysines by a set of different histone acetyl transferases (HATs) and removed by a set
of histone deacetylase complexes (HDACs). Likewise, methyl groups are added to
lysine side chains by a set of different histone methyl transferases and removed
by a set of histone demethylases. Each enzyme is recruited to specific sites on
the chromatin at defined times in each cell’s life history. For the most part, the
initial recruitment depends on transcription regulator proteins (sometimes called
“transcription factors”). As we shall explain in Chapter 7, these proteins recognize
and bind to specific DNA sequences in the chromosomes. They are produced at