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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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