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

976 Chapter 17: The Cell Cycle
not simply a matter of replicating the DNA at its core but also requires the duplication
of these chromatin proteins and their proper assembly on the DNA.
The production of chromatin proteins increases during S phase to provide the
raw materials needed to package the newly synthesized DNA. Most importantly,
S-Cdks stimulate a large increase in the synthesis of the four histone subunits that
form the histone octamers at the core of each nucleosome. These subunits are
assembled into nucleosomes on the DNA by nucleosome assembly factors, which
typically associate with the replication fork and distribute nucleosomes on both
strands of the DNA as they emerge from the DNA synthesis machinery.
Chromatin packaging helps to control gene expression. In some parts of the
chromosome, the chromatin is highly condensed and is called heterochromatin,
whereas in other regions it has a more open structure and is called euchromatin
(discussed in Chapter 4). These differences in chromatin structure depend on a
variety of mechanisms, including modification of histone tails and the presence of
non-histone proteins. Because these differences are important in gene regulation,
DNA
Cdc6
ORC (origin recognition complex)
Cdt1
origin
G 1
Mcm helicase
+
prereplicative complex (preRC)
S
G 2
P
initiator proteins
S-Cdk
DDK
P
P
P
INACTIVATION OF
ORC, Cdc6, Cdt1
DNA HELICASE
ACTIVATION
RECRUITMENT OF DNA POLYMERASE
AND REPLICATION PROTEINS
P
P
P
COMPLETION OF
DNA REPLICATION
P
Figure 17–18 Control of the initiation
of DNA replication. The replication origin
is bound by the ORC throughout the cell
cycle. In early G 1 , Cdc6 associates with
the ORC, and these proteins bind the
DNA helicase, which contains six closely
related subunits called Mcm proteins. The
helicase also associates with a protein
called Cdt1. Using energy provided by ATP
hydrolysis, the ORC and Cdc6 proteins
load two copies of the DNA helicase, in an
inactive form, around the DNA next to the
origin, thereby forming the prereplicative
complex (preRC). At the onset of S
phase, S-Cdk stimulates the assembly
of several initiator proteins on each DNA
helicase, while another protein kinase,
DDK, phosphorylates subunits of the DNA
helicase. As a result, the DNA helicases
are activated and unwind the DNA. DNA
polymerase and other replication proteins
are recruited to the origin, and DNA
replication begins. The ORC is displaced
by the replication machinery and then
rebinds. S-Cdk and other mechanisms
also inactivate the preRC components
ORC, Cdc6, and Cdt1, thereby preventing
formation of new preRCs at the origins until
the end of mitosis (see text).