Cell Nucleus Biogenesis, Structure and Function
385
elements and serve as target sites for
the recruitment of ORC. No equivalent
sequences have been deFned in mul-
ticellular eukaryotes and it is believed
that origins are deFned by a complex
combination of genetic and epigenetic
features.
Duplication of the DNA double helix
proceeds by a semiconservative mecha-
nism. The DNA duplex is Frst opened
to separate the two strands, each of which
then serves as a template to generate two
identical daughter DNA molecules. The
synthetic enzymes responsible for the syn-
thetic process are called
DNA polymerases
(Table 1). Many other proteins are involved
in the replication process (±ig. 1). The crit-
ical Frst step of the replication process,
DNA denaturation is driven by an enzyme
called
DNA helicase
. Helicases unwind the
DNA template. The newly formed single-
stranded regions are stabilized by a DNA-
binding protein called
replication factor-A
(
RF-A
). The DNA replication then begins.
However, DNA polymerases are unable
to initiate the synthetic process-initiation
requires that a DNA dependent RNA
polymerase called
ap
r
im
a
s
e
,F
r
s
tg
e
n
-
erates short (usually about 5 bp) RNA
primers at each replication origin. DNA
polymerase-
α
then proceeds to synthesize
DNA by extending the RNA primer. DNA
polymerase-
α
is not especially processive
(i.e. efFcient at copying long stretches
of DNA) and soon after initiation the
synthetic process is assumed by DNA
polymerases-
δ
and/or -
ε
.
The antiparallel structure of DNA adds
a certain complexity to the replication pro-
cess. Because of the reaction mechanisms
that drive chain elongation, the polymer-
ization process can take place only in one
direction – nucleic acids only grow from
the 5
0
to 3
0
ends. Replication from a sin-
gle origin almost always occurs in two
directions, so that each origin will have
four associated polymerase complexes, two
at each growing replication fork (±ig. 1
shows the proteins at one of the two
forks). At each fork, replication of one
Tab. 1
Eukaryotic DNA polymerases.
Name
Family
Amino acids
Major function
Pol
α
B
1462
Initiates replication
Pol
β
X
335
Base excision repair
Pol
γ
A
1239
Mitochondrial DNA replication
Pol
δ
B
1107
Nuclear DNA replication
Pol
ε
B
3000
Nuclear DNA replication
Pol
ζ
B
3130
Mutagenic synthesis?
Pol
η
Y
713
Translesion synthesis
Pol
θ
A
2724
Cross-link repair?
Pol
ι
Y
715
Specialized base excision repair?
Pol
κ
Y
870
Unknown
Pol
λ
X
575
Base excision repair, meiotic roles
Pol
µ
X
495
ds DNA break repair
Pol
σ
X
543
Sister chromatid cohesion
REV1
Y
1251
Mutagenic translesion DNA synthesis
Note
: See Bebenek, K., Kunkel, T.A. (2002) Family growth: the eukaryotic DNA polymerase revolution,
Cell Mol. Life Sci.
59
,54–57forfurtherdetai
ls.
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