section 24.4
Chromosome Replication
FIGURE 24-11
Hypothetical stages in the condensation of DNA with chromatin to form a
chromosome, (a) Double-stranded DNA. (b)-(e) Formation of nucleosome
beads and fibers consisting of histones and condensed DNA to form (f) a
metaphase chromosome. These proposed intermediates are derived from
dissociation reactions with intact chromosomes.
Despite the dense packing of DNA in chromosomes, it
must be accessible to regulatory proteins during replica-
tion and gene expression. At a higher level of organization,
chromosomes are divided into regions called
Transcription of genes seems to be
confined mainly to euchromatic regions while DNA in het-
erochromatic regions is genetically inactive. When DNA is
replicated during the S phase of the cell cycle, the histone
and nonhistone proteins also are duplicated and combine
with the daughter DNA molecules.
Replication of DNA in Chromosomes
The rate of movement of a replication fork in
E. coli
about 10
nucleotides per minute; in eukaryotes the DNA
polymerases move only about one-tenth as fast. To repli-
cate all of the DNA in a human cell in a few hours means
that replication must be initiated at thousands of origins
of replication in each chromosome and move bidirection-
ally. To accomplish this, mammalian cells have thousands
of times more DNA polymerase available than is found
in bacteria. As replication proceeds through each nucle-
osome, the histones must dissociate to allow the repli-
cation fork to proceed; after replication, the nucleosome
re-forms. The separation of parental and daughter DNA
also requires the synthesis of new nucleosomes. Recent
studies suggest that DNA is replicated in “replication fac-
tories,” i.e., fixed sites within the nucleus consisting of
the numerous proteins needed for replication. The DNA
is replicated by being drawn through the replication facto-
ries rather than having the replication proteins move along
the DNA.
Replication at the Ends of Chromosomes
Since DNA in chromosomes is a linear molecule, prob-
lems arise when replication comes to the ends of the DNA.
Synthesis of the lagging strand at each end of the DNA re-
quires a primer so that replication can proceed in a 5' to 3'
direction. This becomes impossible at the ends of the DNA
and 50-100 bp is lost each time a chromosome replicates.
Thus, at each mitosis of a somatic cell, the DNA in chro-
mosomes becomes shorter and shorter. Ultimately, after a
limited number of divisions, a cell enters a nondividing
state, called
replicative senescence,
which may play an
important role in biological aging.
To prevent the loss of essential genetic information dur-
ing replication, the ends of DNA in chromosomes contain
special structures called
that are synthesized
by a specific enzyme called
Intact telomerase
consists of an RNA primer and associated proteins so
telomerase is actually a reverse transcriptase. The activity
of telomerase in replenishing telomeres is regulated by a
number of telomere-specific DNA-binding proteins, TRF1
and TRF2. TRF1 regulates the length of telomeres and
TRF2 protects the ends. Overexpression of TRFI results
in progressive shortening of telomeres; underexpression
results in lengthening. Another telomere regulatory pro-
tein is
(TRFI-interacting ankvrin-relaled ADP-
ribose polymerase), which alters the activity of TRFI.
Telomeres in human chromosomes consist of tandem
repeats of the sequence TTAGGG. In most adult somatic
cells, telomerase activity is very low or absent. Even in
previous page 587 Bhagavan Medical Biochemistry 2001 read online next page 589 Bhagavan Medical Biochemistry 2001 read online Home Toggle text on/off