388
Cell Nucleus Biogenesis, Structure and Function
in DNA. In this case, the DNA with
a missing base is recognized by the
enzyme AP endonuclease, which then
cuts the DNA phosphodiester backbone
at the 5
0
side of the altered site. The
sugar and phosphate are then removed by
a phosphodiesterase and DNA sequence
restored by DNA polymerase-
β
and DNA
ligase using the complementary DNA
strand as template. Base excision repair
provides an alternative repair pathway that
involves a family of DNA glycosylases.
These enzymes recognize altered bases in
DNA and catalyze their removal so that the
natural DNA sequence can be restored.
Nucleotide excision repair provides a
quite different repair pathway that is ca-
pable of repairing many types of DNA
that distort the structure of DNA. Typi-
cal example of damage that is removed
by this pathway include the thymine
dimers and 6 to 4 photoproducts (C-T
dimers) caused by ultraviolet irradiation
(sunlight) and ‘‘bulky adducts’’ such as
those created by the covalent reaction
of DNA with hydrocarbons like the car-
cinogen benzopyrene. In this case, a
large multienzyme complex scans DNA
for damage and on recognition uses
nucleases to remove a DNA patch of
about 30 bp. Helicase activity (XPD) is
required
to
remove the
DNA
strand
containing the damage and this is then
repaired by DNA polymerase and ligase
using the complementary DNA strand
as template. The process also involves
the transcription factor TFIIH. This is
recruited to the repair site and con-
comitantly leads to a downregulation of
RNA synthesis, which prevents the cell
from attempting transcription of damaged
DNA.
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h
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genome intact cannot be overstated as
many classes of lesion can be mutagenic
and will ultimately lead to cancer. Robust
pathways are in place that minimize the
likelihood of damage leading to cancer. For
example, both ionizing and ultraviolet radi-
ation induce the activity of protein kinases
such as the mammalian ATM protein,
which alters the phosphorylation status
of the protein p53; p53 has been termed
the guardian of the genome
.Th
isenhances
the stability of p53 by reducing its inter-
action with the inhibitor of p53 function
called MDM2 and stimulates the transcrip-
tion factor activities of p53, increasing the
synthesis of p21, an inhibitor of cell cycle
progression, and the proapoptotic protein
BAX. If DNA damage is suf±ciently severe,
the cell is committed to die. The combined
activities of ATM, ATR, chk1, and chk2
also serve to ensure that DNA synthesis
is downregulated, to reduce the possibil-
ity that replication might proceed through
damaged regions of the genome and so ±x
mutations into DNA.
2.3
The Cell Division Cycle
Multicellular organisms must continu-
ously replace cells that are damaged or
have otherwise ful±lled their natural pur-
pose. Cell replacement operates through
a proliferative ‘‘cell cycle’’ during which
mitogenic cues (growth factors) from the
local environment activate a complex se-
ries of events that will ultimately lead each
parental or mother cell to divide into two
genetically identical daughters. The cell
cycle should be viewed as a continuous
process, though for descriptive simplic-
ity it is usually broken down into four
phases – G1, S, G2, and mitosis. Mitosis
is by far the most visibly distinct phase,
which can be watched in living cells us-
ing a simple optical microscope. Mitosis
might be viewed as the culmination of the
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