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Although many
oxidative lesions occur in DNA, 8-hydroxylation
of the guanine base to form 8-hydroxy-2-deoxyguanosine
(8-OHdG) is the predominant such oxidative process
(Ames, 1989). This is a mutagenic lesion because
it produces predominantly G -/ T transversion
mutation (Cheng et al., 1992). Additionally,
8-OHdG accumulates in DNA exposed to ROS (Kasai
and Nishimura, 1986). Because of these characteristics,
8-OHdG is often used as a marker for estimating
ROS-induced DNA damage. Early studies of 8-OHdG
found a 10-fold higher concentration of 8-OHdG
in mitochondrial DNA compared to nuclear DNA
(Richter et. al., 1988). In mouse skeletal muscle,
8-OHdG levels increased with aging (Sohal et.al
1994a).
Selected references
on
DNA damage and faulty DNA repair: |
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2005
Department of Molecular
Genetics, Medical Research Institute,
Tokyo Medical and Dental University, Tokyo,
Japan.
c-Abl is a ubiquitously
expressed tyrosine kinase that participates
in a diverse array of cellular signaling
cascades. The cellular response elicited
by c-Abl depends upon its location in
cells. Retention of c-Abl in the cytoplasm
results in cell proliferation and survival.
By contrast, nuclear c-Abl becomes activated
and induces apoptosis following genotoxic
stress. We recently demonstrated the molecular
mechanisms by which c-Abl shuttles into
the nucleus in response to DNA damage.
In normal cells, 14-3-3 proteins sequester
c-Abl in the cytoplasm. Upon exposure
of cells to DNA damaging agents, JNK is
activated and phosphorylates 14-3-3, resulting
in the release of c-Abl into the nucleus.
Importantly, nuclear targeting of c-Abl
is required for the induction of apoptosis
in response to DNA damage. Thus, c-Abl
may function in determining cell fate
via its subcellular localization. In this
review, we focus on the implications of
these findings on our understanding of
Abl-regulated cellular functions and on
potential therapeutic strategies to manipulate
the aberrant kinase.
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Institute of Molecular
Medicine and Genetics, Medical College
of Georgia Augusta, GA 30912, USA.
Cellular responses
to DNA damage reflect the dynamic integration
of cell cycle control, cell-cell interactions
and tissue-specific patterns of gene regulation
that occurs in vivo but is not recapitulated
in cell culture models. Here we describe
use of the zebrafish embryo as a model
system to identify determinants of the
in vivo response to ionizing radiation-induced
DNA damage. To demonstrate the utility
of the model we cloned and characterized
the embryonic function of the XRCC5 gene,
which encodes Ku80, an essential component
of the nonhomologous end joining pathway
of DNA repair. After the onset of zygotic
transcription, Ku80 mRNA accumulates in
a tissue-specific pattern, which includes
proliferative zones of the retina and
central nervous system. In the absence
of genotoxic stress, zebrafish embryos
with reduced Ku80 function develop normally.
However, low dose irradiation of these
embryos during gastrulation leads to marked
apoptosis throughout the developing central
nervous system. Apoptosis is p53 dependent,
indicating that it is a downstream consequence
of unrepaired DNA damage. Results suggest
that nonhomologous end joining components
mediate DNA repair to promote survival
of irradiated cells during embryogenesis.
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Department of Pharmacology
and Therapeutics, McGill University, 3655
Promenade Sir William Osler, Montreal,
QC, H3G 1Y6, Canada.
DNA damage contributes
significantly to the abnormal development
or demise of the conceptus. The widely
differing phenotypes that result from
mutations in DNA repair genes suggest
that these genes play critical roles during
development, even in the absence of exogenous
DNA-damaging agents. Molecules that sense
DNA damage and regulate DNA repair, cell
cycle checkpoints and apoptosis act as
teratogen suppressor genes, protecting
the conceptus against insult from DNA
damaging teratogens.
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